CA1155115A - Basic ethers, a process for their preparation and pharmaceutical compositions containing same - Google Patents
Basic ethers, a process for their preparation and pharmaceutical compositions containing sameInfo
- Publication number
- CA1155115A CA1155115A CA000366719A CA366719A CA1155115A CA 1155115 A CA1155115 A CA 1155115A CA 000366719 A CA000366719 A CA 000366719A CA 366719 A CA366719 A CA 366719A CA 1155115 A CA1155115 A CA 1155115A
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- bicyclo
- trimethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Anesthesiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to novel basic ethers of the general formula /I/ and pharmaceutically acceptable acid addition salts and quaternary salt, thereof, /I/
wherein R1 and R2 may be the same or different and represent a C1-5 alkyl group or a C3-6 cycloalkyl group or they form, together with the adjacent nitrogen atom, a heterocyclic ring containing 4-7 carbon atoms and optionally a further hetero atom, e.g. an oxygen, sulfur or nitrogen atom, and his latter may be optionally substituted by a C1-3 alkyl, benzyl or phenyl group, R represents a phenyl, phenyl-/C1-3 alkyl/ or ? group ? substituted by one or more halogen or C1-3 ? ? substituent/s/, A represents a C2-5 straight or branched alkylene chain, and ? represents a valence bond of ? or .beta. configuration.
The compounds of the general formula /I/ are prepared according to the invention a./ by reacting a compound of the general formula /II/
/II/
wherein R has the same meaning as above, whereas R3 denotes an alkali metal atom, an alkali-earth metal atom or a group of the general formula ?-Me, wherein ? denotes halogen and Me stands for alkali-earth metal atom, with a compound of the general formula /III/
/III/
wherein Y stands for halogen and A, R1 and R2 have the same meaning as above; or b./ by treating a compound of the general formula /IV/
/IV/
wherein R has the same ? ? as above, with an agent suitable ? ? produce as R3 group and reacting the compound of the general formula /II/ thus obtained, wherein R and R3 have the above-defined ?, with a compound of the general ? ? /III/; or c./ by reacting 1,7,7-trimethy-bicycle/2.2.1/ ?-2-one of the formula /V/ with ? as ? -metallic compound, decomposing the complex thus obtained, and reacting the compound of the general formula /IV/ thus obtained, wherein R has the above defined meaning, with a base suitable to introduce an R3 group, and reacting the compound of the general formula /II/
thus obtained with a compound of the general formula /III/, and, if desired, converting the compound of the general formula /I/ thus obtained into a pharmaceutically acceptable acid addition salt or quaternary salt.
The new compounds of the general formula /I/ possess valuable anticonvulsive, motility inhibiting, hexobarbital narcose potentiating and analgesic effects, which are, in case of certain compounds, complemented by weak antiserotonine, gastro-intestinal-tract inhibiting and antiinflammatory effects, and can be applied to advantage in the therapy.
The invention relates to novel basic ethers of the general formula /I/ and pharmaceutically acceptable acid addition salts and quaternary salt, thereof, /I/
wherein R1 and R2 may be the same or different and represent a C1-5 alkyl group or a C3-6 cycloalkyl group or they form, together with the adjacent nitrogen atom, a heterocyclic ring containing 4-7 carbon atoms and optionally a further hetero atom, e.g. an oxygen, sulfur or nitrogen atom, and his latter may be optionally substituted by a C1-3 alkyl, benzyl or phenyl group, R represents a phenyl, phenyl-/C1-3 alkyl/ or ? group ? substituted by one or more halogen or C1-3 ? ? substituent/s/, A represents a C2-5 straight or branched alkylene chain, and ? represents a valence bond of ? or .beta. configuration.
The compounds of the general formula /I/ are prepared according to the invention a./ by reacting a compound of the general formula /II/
/II/
wherein R has the same meaning as above, whereas R3 denotes an alkali metal atom, an alkali-earth metal atom or a group of the general formula ?-Me, wherein ? denotes halogen and Me stands for alkali-earth metal atom, with a compound of the general formula /III/
/III/
wherein Y stands for halogen and A, R1 and R2 have the same meaning as above; or b./ by treating a compound of the general formula /IV/
/IV/
wherein R has the same ? ? as above, with an agent suitable ? ? produce as R3 group and reacting the compound of the general formula /II/ thus obtained, wherein R and R3 have the above-defined ?, with a compound of the general ? ? /III/; or c./ by reacting 1,7,7-trimethy-bicycle/2.2.1/ ?-2-one of the formula /V/ with ? as ? -metallic compound, decomposing the complex thus obtained, and reacting the compound of the general formula /IV/ thus obtained, wherein R has the above defined meaning, with a base suitable to introduce an R3 group, and reacting the compound of the general formula /II/
thus obtained with a compound of the general formula /III/, and, if desired, converting the compound of the general formula /I/ thus obtained into a pharmaceutically acceptable acid addition salt or quaternary salt.
The new compounds of the general formula /I/ possess valuable anticonvulsive, motility inhibiting, hexobarbital narcose potentiating and analgesic effects, which are, in case of certain compounds, complemented by weak antiserotonine, gastro-intestinal-tract inhibiting and antiinflammatory effects, and can be applied to advantage in the therapy.
Description
i51~S
This invention relates to novel basic ethers of valuable therapeutic effect and to a process for their preparation. The invention relates also to pharmaceutical compositions containing the said compounds.
According to a feature of the present invention there are provided compounds of the general formula I
H3C ~ CH3 \ R
and pharmaceutically acceptable acid addition salts and quaternary salts, thereof, wherein R and R may be the same or different and represent a Cl 5 alkyl group or a C3 6 cycloalkyl group or they form, together with the adjacent nitrogen atom, a saturated S-, 6- or 7-membered heterocyclic ring which option-ally contains a further hetero atom which is an oxygen, sulfur or nitrogen atom;
R represents a phenyl, phenyl-(Cl 3 alkyl) or thienyl group ~ -- 1 --D~
: . . . ~ ,.. .
:~liS5~1S
optionally sub~tituted by one or more halogen or Cl 3 alkoxy substituent/s/, A represents a C2_5 straight or branched alkylene chain, and ~v represents a valenco bond of o~ or ~ configuration, ~he invention also embraces all steric isomers o~ the compounds of the general formula /I/ and the mi~tures thereof.
The compounds of the general formula /I/ contain, depending on the definition of the substituents, two or more centres of asymmetry, consequently they exist in the form of one or more raoemic mixture/s/ or two or more optically active antipodes.
~he invention embraces the racemic and optically active forms o~ the compounds of the general formula /I/, too.
~he term "Cl 5 alkyl group" relates to straight or branched ~aturated aliphatic hydrocarbyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc, ~he term "C3 6 cycloalkyl group" may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group. ~he heterocyclic ring ~ormed by Rl, R2 and the adjacent nitrogen atom may be piperidine, pyrrolidine, morpholine, thiomorpholine, piperazine, N-methyl-piperazine, N-phenyl-piperazine or N-benzyl-piperazine, etc, ~he term "phenyl-/Cl 3alkyl/ group may be benzyl or ~ -phenylethyl group, The term "C1 3 alkoxy group" r~lates to straight or branched lower alkylether groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, etc, ~he term "halogen atom"
may ~tand for all the ~our halogen atoms, such as fluorine, chlorine, iodine, bromine, ~he term "~2 5 alkenyl group" refer~
to ~traight or branched lower alkenyl group~ such as ethylene, propylene, 2-methyl-propylene, butylene, 2-methyl-buthylene, etc.
`:
,:
55~5 Pre~erred representatives o~ the new compounds having the general ~ormula /I/ are those wherein Rl and R2 each represent methyl or ethyl group, R denotes phenyl, benæyl or Cl 3-alkoxy-phenyl group, and A denotes ethylene, propylene or 2-methyl-propylene group.
Of the new compounds o~ the general formula /I/ the ~ollowing are particularly preferred:
This invention relates to novel basic ethers of valuable therapeutic effect and to a process for their preparation. The invention relates also to pharmaceutical compositions containing the said compounds.
According to a feature of the present invention there are provided compounds of the general formula I
H3C ~ CH3 \ R
and pharmaceutically acceptable acid addition salts and quaternary salts, thereof, wherein R and R may be the same or different and represent a Cl 5 alkyl group or a C3 6 cycloalkyl group or they form, together with the adjacent nitrogen atom, a saturated S-, 6- or 7-membered heterocyclic ring which option-ally contains a further hetero atom which is an oxygen, sulfur or nitrogen atom;
R represents a phenyl, phenyl-(Cl 3 alkyl) or thienyl group ~ -- 1 --D~
: . . . ~ ,.. .
:~liS5~1S
optionally sub~tituted by one or more halogen or Cl 3 alkoxy substituent/s/, A represents a C2_5 straight or branched alkylene chain, and ~v represents a valenco bond of o~ or ~ configuration, ~he invention also embraces all steric isomers o~ the compounds of the general formula /I/ and the mi~tures thereof.
The compounds of the general formula /I/ contain, depending on the definition of the substituents, two or more centres of asymmetry, consequently they exist in the form of one or more raoemic mixture/s/ or two or more optically active antipodes.
~he invention embraces the racemic and optically active forms o~ the compounds of the general formula /I/, too.
~he term "Cl 5 alkyl group" relates to straight or branched ~aturated aliphatic hydrocarbyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc, ~he term "C3 6 cycloalkyl group" may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group. ~he heterocyclic ring ~ormed by Rl, R2 and the adjacent nitrogen atom may be piperidine, pyrrolidine, morpholine, thiomorpholine, piperazine, N-methyl-piperazine, N-phenyl-piperazine or N-benzyl-piperazine, etc, ~he term "phenyl-/Cl 3alkyl/ group may be benzyl or ~ -phenylethyl group, The term "C1 3 alkoxy group" r~lates to straight or branched lower alkylether groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, etc, ~he term "halogen atom"
may ~tand for all the ~our halogen atoms, such as fluorine, chlorine, iodine, bromine, ~he term "~2 5 alkenyl group" refer~
to ~traight or branched lower alkenyl group~ such as ethylene, propylene, 2-methyl-propylene, butylene, 2-methyl-buthylene, etc.
`:
,:
55~5 Pre~erred representatives o~ the new compounds having the general ~ormula /I/ are those wherein Rl and R2 each represent methyl or ethyl group, R denotes phenyl, benæyl or Cl 3-alkoxy-phenyl group, and A denotes ethylene, propylene or 2-methyl-propylene group.
Of the new compounds o~ the general formula /I/ the ~ollowing are particularly preferred:
2-benzyl-2-/3'-dimethylamino-2'-methyl-propoxy/-1,7,7-trimethyl-bicyclo/2.2,1/heptane, 2-benzyl-2-/3'-diethylaminopropoxy/-1,7,7_trimethyl_bicyclo_ /2.2.1/heptane, 2-benzyl-2-/2'-diethylaminoethoxy/-1,7,7-trimethyl-bicyclo-/2.2.1/heptane, and the pharmaceutically acceptable acid addition salts o~
these compounds, The ~ollowing representatives o~ the compounds o~ the general ~ormula /I/ have the most valuable pharmaceutical activities:
2-phenyl-2-/3?-dimethylaminopropoxy/-1,7,7-trimethyl-bicyclo-~2.2.1/heptane, 2-phenyl-2-/2'-dimethylaminoethoxy/-1,7,7-trimethyl-bicyclo-/2.2.1/ heptane, 2-phenyl-2-/3'-diethylami~opropoxy/-1,7,7-trimethyl-bicyclo-/2.2.1/ heptane, 2-/p-methoxy-phenyl/-2-/3'-dimethylaminopropoxy/-1,7,7-tri-methyl-bicyclo/2,2.1/ heptane, and pharmaceutically acceptable acid addition salts o~ these compounds, ~he pharmaceutically acceptable acid addition salts o~
the compounds o~ the general ~ormula /I/ can be ~ormed with .
.
~lS51~5 inorganic or organic acids generally uæed for this purpose, e,g. with hydrogen chloride, hydrogen bromide, sulfuxic, phosphoric, acetic, lactic, propionic, methanesulfonic, tartaric, maleic, fumaric acids, etc, ~he quaternary salts of the compounds of the general formula /I/ can be ~ormed with reactants usually applied for quaternarisation, e.g, with lower alkyl halogenides, such as methyl iodide or methyl chloride, dialkyl-sulfates, such as diethylsulfate, n-propyl lodide, etc, According to a further feature of the present invention there is provided a process for the preparation of basic ethers of the general formula /I/ and pharmaceutically acceptable acid addition salts and quaternar~ salts thereo~, which comprises a./ reacting a compound o~ the general ~o~mula /II/
~ 3C ~ C ~ 3 ~ ~ /II/
~/ ~
t 13C R -R3 wherein R has the same meaning as above, wherea~
R3 denote~ an alkali metal atom, an alkali-earth metal atom or a group o~ the general ~ormula X-Me, wherein X denotes halogen and Me stands for alkali-earth metal atom, with a compound of the general formula /III/
Rl Y - A - N ~ /III/
wherein Y stands ~or halogen and A, Rl and R2 have the same 1155ilS
meaning as above; or b./ treating a compound of the general ~ormula /IV/
~3C ~ C ~3 1~
/IV/
H~ 01~
wherein R has the same meaning as above, with an agent suitable to introduce an R3 group and reacting the compound of the general formula /II/ thus-obtained, wherein ~R and R3 have the above-de~ined meanings, with a oompound o~
; the general formula /III/;` or c./ r~acting 1.7.7-trimethyl-bioyclo/2.2.1theptane-2-one with an organo-metallic compound, decompoæing ~; 15 the complex thuæ-obtained, and reacting the compound of the general formula /IV/ thua obtained, wherein R has~the above defined~meaning, with a ba~e æuitable to i~troduce an R3 group, and react~lng the compound o~ the general formula ~II/ !
thu~æ obtained with a compound of the general formula /III/, and, if desired, convarting the compound of the general formuIa /I/ thuæ obtained into a pharmaceutically acceptable acid addition salt or quaternary ~alt.
he rea¢tion o~ oompou ~ of the general ~ormu~ /II/
and /III/ oan be oarried out in an organio solvent, ~uch as benzene, toluene, xylene, dimethylacetamide, dimethylsulfo~ide, dimethylformamide, tetrahydrofurane or the mixture thereof.
~he reaction oan be per~ormed in a wide temperature range, e.g. from -10 C to 200 C, preferably at a temperature between 10 a and 100 C.
~ 30 The compounds af the general formula /I/ can be isolated : ~ :
.
.~. . . .:
~1~5~5 ~rom the reaction mixture by methods ~nown Per se, e.g.
evaporating the reaction mixture, extracting with a suitable organic solvent, etc, The compounds o~ the general ~ormula /II/ can be prepared by rèacting a compound of the general formula /IV/ with a reactant suitable to introduce an R3 group. Alkali metals /e,g, lithium, sodium or potassium/ and hydrides or amides o~ the respective metals /e.g. sodium hydride, potassium hydride, sodium amide, potassium amide, etc./ are pre~erably used ~or this purpose.
The compounds of the general ~ormula /IV/ can be produced by reacting 1,7,7-trimethyl-bicyclo/2.2.1/heptane-2-one of the ~ormula /V/ with an organo-metallic compound and d~compo3~ng the complex thus-obtained, As organo-metallic oompounds sodium- or lithium-compound~ o~ Grignard-reagen~ can be applied. The organo-metallic compound contain~ an organic radical oo~p~ing to the R3group. The reaction can be performed in t~n inert solvent in a known matter. As reaction medium, diethylether, tetrahydro~urane, dii~opropylether, benzene, petrolether, etc.
can be applied. The reaction temperature can be ranged in a wide interval. The reaction can pre~erably carried out between 1 C and1~0 C~
Aocordin~t to a pre~erred method o~ the lnrention the starting compound of the general formula /II/ prepared by reacting a compound of the general formula /IV/ with a reagent suitable to introduce an R group i~ not isolated, but the compound o* the general ~ormula ~III/ is added to the reaction mixture containing the compound of the general formula /II/.
The compound o~ the general formula /V/ i~ a commercial ~0 product, The starting compounds o~ the general ~ormula /III/
., ,;
~t ~155 are known products, The acid addition salts and quaternary salts of the compounds of the general ~ormula /I/ can be prepared by methods known per se. ~o prepare an acid addition salt a base o~ the general ~ormula /I/ is reacted with optionally one mole-equivalent amount of the respective acid. ~o prepare a quaternary salt a base o~ the general ~ormula /I/ is reacted with optionally one mole-equivalent amount o~ the respec-tive quaternarising agent in an organic solvent.
~he optically active antipodes of the ~eneral ~ormula /I/ can be prepared by using optically active s-tarting compounds or by resolving the respective racemic compound by a method known ~er se. ~or this purpose a racemic compound o~ the general formula /I/ is reacted with an optically active acid, such as tartaric acid, 0,0-dibenzoyl-tartaric acid, 0,0-di-p-to~ne-tartaric acid or camphor-sulfonic acid, the diastereomeric salt-pair thus-obtained is separated by ~ractionated crystallisation, and the optically active isomer is liberated ~rom the salt by reacting it with a base under mild conditions. ~he fractionated ~tallisation can be carried out in a suitable solvent, e.g. methanol, water, etc, ~ccording to our investigation~ the compounds o~ the general formula /I/ pro~ed to be biologically active in ~everal te~ts and po~e~s particularly tranquillizing, anti-parkinson, analgesic and antiepileptic e~ects. Of these biological e~fects the most significants were: the anti-convulsive, motility inhibiting, hexobarbital-narco~i9 potentiating and analgesic e~fects which are, in case o~
certain compounds, complemented by week antiserotonine,
these compounds, The ~ollowing representatives o~ the compounds o~ the general ~ormula /I/ have the most valuable pharmaceutical activities:
2-phenyl-2-/3?-dimethylaminopropoxy/-1,7,7-trimethyl-bicyclo-~2.2.1/heptane, 2-phenyl-2-/2'-dimethylaminoethoxy/-1,7,7-trimethyl-bicyclo-/2.2.1/ heptane, 2-phenyl-2-/3'-diethylami~opropoxy/-1,7,7-trimethyl-bicyclo-/2.2.1/ heptane, 2-/p-methoxy-phenyl/-2-/3'-dimethylaminopropoxy/-1,7,7-tri-methyl-bicyclo/2,2.1/ heptane, and pharmaceutically acceptable acid addition salts o~ these compounds, ~he pharmaceutically acceptable acid addition salts o~
the compounds o~ the general ~ormula /I/ can be ~ormed with .
.
~lS51~5 inorganic or organic acids generally uæed for this purpose, e,g. with hydrogen chloride, hydrogen bromide, sulfuxic, phosphoric, acetic, lactic, propionic, methanesulfonic, tartaric, maleic, fumaric acids, etc, ~he quaternary salts of the compounds of the general formula /I/ can be ~ormed with reactants usually applied for quaternarisation, e.g, with lower alkyl halogenides, such as methyl iodide or methyl chloride, dialkyl-sulfates, such as diethylsulfate, n-propyl lodide, etc, According to a further feature of the present invention there is provided a process for the preparation of basic ethers of the general formula /I/ and pharmaceutically acceptable acid addition salts and quaternar~ salts thereo~, which comprises a./ reacting a compound o~ the general ~o~mula /II/
~ 3C ~ C ~ 3 ~ ~ /II/
~/ ~
t 13C R -R3 wherein R has the same meaning as above, wherea~
R3 denote~ an alkali metal atom, an alkali-earth metal atom or a group o~ the general ~ormula X-Me, wherein X denotes halogen and Me stands for alkali-earth metal atom, with a compound of the general formula /III/
Rl Y - A - N ~ /III/
wherein Y stands ~or halogen and A, Rl and R2 have the same 1155ilS
meaning as above; or b./ treating a compound of the general ~ormula /IV/
~3C ~ C ~3 1~
/IV/
H~ 01~
wherein R has the same meaning as above, with an agent suitable to introduce an R3 group and reacting the compound of the general formula /II/ thus-obtained, wherein ~R and R3 have the above-de~ined meanings, with a oompound o~
; the general formula /III/;` or c./ r~acting 1.7.7-trimethyl-bioyclo/2.2.1theptane-2-one with an organo-metallic compound, decompoæing ~; 15 the complex thuæ-obtained, and reacting the compound of the general formula /IV/ thua obtained, wherein R has~the above defined~meaning, with a ba~e æuitable to i~troduce an R3 group, and react~lng the compound o~ the general formula ~II/ !
thu~æ obtained with a compound of the general formula /III/, and, if desired, convarting the compound of the general formuIa /I/ thuæ obtained into a pharmaceutically acceptable acid addition salt or quaternary ~alt.
he rea¢tion o~ oompou ~ of the general ~ormu~ /II/
and /III/ oan be oarried out in an organio solvent, ~uch as benzene, toluene, xylene, dimethylacetamide, dimethylsulfo~ide, dimethylformamide, tetrahydrofurane or the mixture thereof.
~he reaction oan be per~ormed in a wide temperature range, e.g. from -10 C to 200 C, preferably at a temperature between 10 a and 100 C.
~ 30 The compounds af the general formula /I/ can be isolated : ~ :
.
.~. . . .:
~1~5~5 ~rom the reaction mixture by methods ~nown Per se, e.g.
evaporating the reaction mixture, extracting with a suitable organic solvent, etc, The compounds o~ the general ~ormula /II/ can be prepared by rèacting a compound of the general formula /IV/ with a reactant suitable to introduce an R3 group. Alkali metals /e,g, lithium, sodium or potassium/ and hydrides or amides o~ the respective metals /e.g. sodium hydride, potassium hydride, sodium amide, potassium amide, etc./ are pre~erably used ~or this purpose.
The compounds of the general ~ormula /IV/ can be produced by reacting 1,7,7-trimethyl-bicyclo/2.2.1/heptane-2-one of the ~ormula /V/ with an organo-metallic compound and d~compo3~ng the complex thus-obtained, As organo-metallic oompounds sodium- or lithium-compound~ o~ Grignard-reagen~ can be applied. The organo-metallic compound contain~ an organic radical oo~p~ing to the R3group. The reaction can be performed in t~n inert solvent in a known matter. As reaction medium, diethylether, tetrahydro~urane, dii~opropylether, benzene, petrolether, etc.
can be applied. The reaction temperature can be ranged in a wide interval. The reaction can pre~erably carried out between 1 C and1~0 C~
Aocordin~t to a pre~erred method o~ the lnrention the starting compound of the general formula /II/ prepared by reacting a compound of the general formula /IV/ with a reagent suitable to introduce an R group i~ not isolated, but the compound o* the general ~ormula ~III/ is added to the reaction mixture containing the compound of the general formula /II/.
The compound o~ the general formula /V/ i~ a commercial ~0 product, The starting compounds o~ the general ~ormula /III/
., ,;
~t ~155 are known products, The acid addition salts and quaternary salts of the compounds of the general ~ormula /I/ can be prepared by methods known per se. ~o prepare an acid addition salt a base o~ the general ~ormula /I/ is reacted with optionally one mole-equivalent amount of the respective acid. ~o prepare a quaternary salt a base o~ the general ~ormula /I/ is reacted with optionally one mole-equivalent amount o~ the respec-tive quaternarising agent in an organic solvent.
~he optically active antipodes of the ~eneral ~ormula /I/ can be prepared by using optically active s-tarting compounds or by resolving the respective racemic compound by a method known ~er se. ~or this purpose a racemic compound o~ the general formula /I/ is reacted with an optically active acid, such as tartaric acid, 0,0-dibenzoyl-tartaric acid, 0,0-di-p-to~ne-tartaric acid or camphor-sulfonic acid, the diastereomeric salt-pair thus-obtained is separated by ~ractionated crystallisation, and the optically active isomer is liberated ~rom the salt by reacting it with a base under mild conditions. ~he fractionated ~tallisation can be carried out in a suitable solvent, e.g. methanol, water, etc, ~ccording to our investigation~ the compounds o~ the general formula /I/ pro~ed to be biologically active in ~everal te~ts and po~e~s particularly tranquillizing, anti-parkinson, analgesic and antiepileptic e~ects. Of these biological e~fects the most significants were: the anti-convulsive, motility inhibiting, hexobarbital-narco~i9 potentiating and analgesic e~fects which are, in case o~
certain compounds, complemented by week antiserotonine,
3 gastro-intestinal-tract inhibiting and antiin~lammatory ~155~15 .
effects.
The analgesic effect of the new compounds according to the invention was determined by the method of Wirth et al. /Wirth, W., Gosswald, R., Horlein. ~., Risse, Kl. H., Kreiskott, H.: Arch. Int. Pharmacodyn~ 115, 1 /1958//.
0.4 ml of 0.5 % acetic acid was administered i,p. to white mice, and the eharacteristic "writhing" reactions were counted after 5 minutes. ~he compounds to be tested had been orally administered an hour before the administ~ation of the acetic acid. ~he activity is expressed as a percentage of the inhibition referred to the data observed on the control group. ~he results are given in ~able I. ~he toxicity data determined on white mice of both se~es we~ng 18-24 g belonging to the strain C~LP are also given.
Administration was effected with an oral dosa of 20 ml/kg.
A~ter treatment the animals were kept under observation for 4 days. ~he toxici~y data /LD50 mg/kg/ were determined by the graphic method of ~itchfield-Wilcoxon / Litchfield, J.~.,Wilcoxon, ~ ~, J. Pharmacol. Exp. Therap. 96, 99 /1949/ 7.
:.
' ~L:lS5115 _ g _ Table I
Compound ~D50 Anal~esic ef~ect No. o~ Example ~ mg/kg ED50 mg/kg ~herap.indeg 1 1600 120 13.3 2 1700 85 20.0 3 1250 120 10.4
effects.
The analgesic effect of the new compounds according to the invention was determined by the method of Wirth et al. /Wirth, W., Gosswald, R., Horlein. ~., Risse, Kl. H., Kreiskott, H.: Arch. Int. Pharmacodyn~ 115, 1 /1958//.
0.4 ml of 0.5 % acetic acid was administered i,p. to white mice, and the eharacteristic "writhing" reactions were counted after 5 minutes. ~he compounds to be tested had been orally administered an hour before the administ~ation of the acetic acid. ~he activity is expressed as a percentage of the inhibition referred to the data observed on the control group. ~he results are given in ~able I. ~he toxicity data determined on white mice of both se~es we~ng 18-24 g belonging to the strain C~LP are also given.
Administration was effected with an oral dosa of 20 ml/kg.
A~ter treatment the animals were kept under observation for 4 days. ~he toxici~y data /LD50 mg/kg/ were determined by the graphic method of ~itchfield-Wilcoxon / Litchfield, J.~.,Wilcoxon, ~ ~, J. Pharmacol. Exp. Therap. 96, 99 /1949/ 7.
:.
' ~L:lS5115 _ g _ Table I
Compound ~D50 Anal~esic ef~ect No. o~ Example ~ mg/kg ED50 mg/kg ~herap.indeg 1 1600 120 13.3 2 1700 85 20.0 3 1250 120 10.4
4 2000 200 10.0 2000 100 20.0 6 2000 50 40.0 7 1200 70 17.1 8 850 45 18.9 11 1500 75 20.0 12 2000 100 20.0 13 2000 200 10.0 14 1000 50 20,0 ~5 900 23 39.0 16 700 70 lO.o 17 980 50 19.6 18 1400 1~0 10.0 19 1000 120 8,3 22 1000 72 13.8 Paracetamole510 180 2.8 C~-~4-Hydroxyphenyl)_ -aoetamide~
~ 50 Therapeutic index =
The antiepileptic effect was investigated on white mice, after oral administration. The inhibition o~ maximal f ' I
~ ..
~ ~55~15 electroshock /MES/ was determined by the method o~ Swinyard et al. /~Swinyard et al. J. Pharmacol. E~p. ~her. 106, 319-330 /1952/ 7, White mice weighing 20-25 g were subjected to electric shock through corneal electr~s /Parameters:
50 Hz, 45 mA, 0.4 sec./. ~he total i~hibition o~ the tonic extensor convulsion was considered as criterion o~ the antî-convul~ive e~ect. ~he test-substance had been orally administered one hour be~ore the electroshock. ~he inhi~ition of pentetrazole convulsion was determined on white mice by the modified method o~ ~anziger and Hane / ~anziger, R., Hane, L.D. Arch. Int. Pharmacodyn. 167, 245-249 /1967/ ~.
The results are given in ~able I~ ~hereio "~h. I-" staodo ior "therapeutical inde~n.
~able II
-- Inhibition o~
Compound ~E9 ~ on No. of Example ~D50 mg/kg ~-~Fb~ 5 Wt~ r-1 130 12,3 2 lZ0 14.2 88 19.3 20 ` 5 380 5.3 140 14.3 6 120 16.7 54 37.0 7 56 21.4 66 18.2 8 30 28.3 20 42.5 12 72 27.7 110 18.2 13 140 14.3 140 14.3 16 30 23.3 60 11,7 17 _ _ 60 16.3 22 - - 96 10.4 Trimethadion 4.90 4,3 400 5.3 ~,5,5-Trimethy1-2 4--oxazoli~inedione~
;,t' /Ptim~l/
,.
L5~ S
~he inhibition of nicotine-le-thality was determined on white mice by the method of Stone / Stone, C.A., Mecklenburg, K.L., ~orchiana, M.L., Arch. Int, Pharmacodyn. 117, 419 /1958/~7, One hour a~ter the oral administration of the test-substance 1.4 mg/kg nicotine were injected and the number of the animalæ which suffered from convulsions or died was registered. ~he result~ are given in ~able III.
Table III
.
Compound ED ~herapeutic ~o. of Example mg/5g indeg :
1 38 42.1 2 20 85,0 7 25 48.0 8 11 77.3 30.0 17 50 19.6 ~rihexyphenidyl 40 9.13 (a-Cyolohe~rl-a-phe~y~-l-; 20 -piperidine-propanol~
(Ar~ace) ~he effect on the inhibition of the orie~tal activity /inhibition of the motility/ wa~ inve~tigated on white mice in a Dew~ app~ratus applied with 8 canal~ by the method of ~orsy / ~or~y, J., Cs~nyi, E., ~azar, I., Arc. Int. Pharmaco-dyn. 124, 1-2 /1960/ 7. After an oral pretreatment of 30 minute~ the number o~ light-interruptions due to the movement~
of groups con~isting o~ 3-3 mice was regi~tered. ~he observation lasted ~or 30 minute~. ~he ef~ect o~ the compounds exerted ,~.
~155~1S
on the duration of hexobarbita~ narcosis was tested by the method of Kaergaard /~Kaergaard, N.C., Magnussen, M. P., Kampmann, E., ~rey, H.H., Arc. Int. Pharmacodyn. 2, 170 /1967/ 7. Groups of animals consisting of 6-6 mice were treated. 20 ml/kg of 0.9 % sodium chloride solution were administered to the animals of the control group, then 40 mg/kg o~ hexobarbital were injected, i,v. Those animals of the treated group were considered to be of a positive reaction which showed a sleeping period being at least 2,5 times longer then the sleeping period of the control group.
~he results are given in lable IV.
~able IV
Compound Inhibition of Potentiating of ~o, of Examplemotility narcosi~
ED50 mg/kg ~h.I.ED50 mg/kg Th.I
1 110 14~5 90 17.7 2 _ _ 15 113.3 7 go 13.3 3 - - 120 10.4 190 10.5 120 16,7 6 100 20.0 80 25.0 8 60 14.2 60 14.2 11 130 11.5 130 11.5 12 - _ 200 10.0 13 170 11.8 _ _ 14 38 26.3 64 15,6 - - 40 22.5 16 _ 20 35.0 19 - - 50 20.0 22 100 10.0 80 12.5 Meprobamate 270 4.1 250 4.4 ~r (2-~thyl-2-propyl--1,3-propanediol ?
.. . .
.
. . .. -.: . ... , ~ ;`;,... .
~55115 ~he compounds of the general formula /I/ and therapeutically acceptable acid addition salts and quaternary salts thereo~
ca~ be formulated with the use o~ additives and/or carriers and/or adjuvants generally u~ed in pharmacy, by standard techniques.
According to a ~urther ~eature of the present invention there are provided the above pharmaceutical compositions which can be formulated in solid /e.g. tablets, capsules, coated pills, etc./ or liquid /e.g. solutions, suspensions, emulsions, etc./ form. ~hese pharmaceutical compositions can be administered orally /e.g. tablets, coated pills, capsules, solutions, etc./, rectally /e.g. suppositories/, or parenterally /e.g. injections/, The carriers may be such generally used in pharmacy /e,g. starch, magnesium stearate, calcium carbonate, poly-vinylpyrrolidone, gelatine, lactose, glucose, water, etc./.
The compositions may also contain suitable additives /e.g.
emulsi~ying, suspensing, disintegrating agents, buf~ers, etc,/
~he daily oral dose of the compounds of the general formula /I/ amounts approximately to about 0.25-75 mg. ~hese values are, however, nearly of an in~ormative character and the actually applied dose depends on the circumstances of the given case and the prescription of the physiclan and may lay below or above the ~aid interval.
~he invention is illustrated by the following Examples of non-limiting character:
E:EamPle 1 Pre~aration o~ 2-benzyl-2-/3'-dimethylaminopropoxy/-1,7,7-trimethyl-bicyclo/2.2.1/ heptane ~rl llS5115 _ 14 --A suspension o~ 3.9 g /0.1 moleJ of sodium amide in 100 ml of anhydrous benzene is heated to boiling, and a solution of 24.4 g /0.1 mole/ of /~/-2-benzyl-1,7,7-trimethyl-bicyclo/2,2.1/-hept~ n-2-ol in 100 ml of anhydrous benzene is added dropwise, under continuous stirring. When the addition of the above solution is completed the reaction miæture is boiled until the formation of ammonia gas is ceased, and while further continuing the ætirring, a solution of 13.4 g /0.11 mole/ of 1-dimethylamino-3-chloro-propane in 20 ml of anhydrous benzene is added. After boiling the mixture for further 6 hours it is cooled to 30 C, washed three times with 40 ml of water each, and extracted with a solution of 15 g /0,1 mole/ o~ tartaric acid in 50 ml of water or with 0.11 mole of diluted aqueous hydrochloric acid. ~he aqu~us solution cooled to 0-5 C is made alkaline to pH 10 with concentrated ammonium hydroxide. ~he base separated as an oil is extracted with dichloroethane, On distilling o~f the solvant, the residue is fractionated in vacuo, Yield: 30.2 g /92 %/ of a pale yellow oil . p.: 140-146 C/26.7 Pa Pre~ar~tion of the hydro~en fumarate:
16.5 g /0.05 moles/ o~ the above base dissolved in 20 ml of acetone are added to a solution of 5~8 g /0.05 mole/
of fumaric acid in 60 ml of hot water. On cooling the reaction mixture the separated crystals are filtered off and dried.
Yield: 20.5 g /92 ~/
M.p,: 103-104 C
.~1 . ~
- .
r octanol K ~water ) - 6.4 = partition coef~icient Analysis for C26H39N05 /445.606/:
Calculated: C: 70.08 % ~: 8.82 % N: 3,14 %
~ound: C: 69.04 % ~: 9.02 % N: 3.09 %
Preparation of the hydrogen chloride:
A solution of 3.3 g /0.01 mole/ of the above base in 25 ml of anhydrous ethylacetate is acidi~ied to pH 5 with ethylacetate ~aturated with hydrochloric acid. The separated cr~stals are ~iltered o~f and dried, Yield: 3.5 g /95 %/
M.p.: 146-148 C
Analysis for C22H36ClN0 /365.99/:
Calculated: C: 72,19 % H: 9.90 % Cl: 9.69 N:3.83 %
~ound: C: 72.01 % H: 9,78 % Cl: 9.67 ~:3380 %
Prearation of the citrate:
A solution of 3.8 g /0.02 moles/ of citric acid in 30 ml o~ ethanol is added to a solution of 6.6 ~ tO.02 moles/
of the above base in 10 ml o~ acetone. The separated salt i~ ~iltered o~f and dried, Yield: 9.59 g /89 %/
M.p.: 131-133 C
Analysis for C28H45N2 /539 Calculated: C: 62.31 % H: 8.40 % N: 2.60 %
~ound: C: 62,13 % H: 8,27 % N: 2.68 %
Pre~aration of the tartarate:
A solution of 3.0 g /0.02 moles/ oftartaric acid in 30 ml o~ ethanol is added to a solution of 6.6 g /0.02 moles/
X , ,.
.
:;
~5~15 of the above b~æ ~ lOml of acetone. ~he separated salt is ~iltered o~f and dried.
Yield: 8.82 g /92 %/
M.p.: 92-94 C
Analysis ~or C26H41N07 /479,62/:
Calculated: C: 65.11 % H: 8.62 % N: 2,92 %
~ound: C: 65,37 % H: 8.73 % N: 2v87 %
Pre~aration of the iodometh~late:
A solution o~ 2.82 g /0.02 mol~ o~ methyl iodide in 50 ml o~ acetone is added to a solution of 6.6 g /0.02 mole/ o~ the above base in 50n~o~ acetone, then the reaction mixture is allowed to stand at room-temperature for a night.
~he separated salt is ~iltered o~ and dried.
Yield: 8.3 g /88 %/
M.p,: 187-189 C /decomp./
Analysis for C23H38IN0 /471.48/:
Calculated: C: 58,59 % H: 8.12 % I: 26.92 % N: 2.97 %
~ound: C 58.68 % H: 8.24 % I: 27.05 % N: 2.93 %
Examle 2 Pre~aration o~ ~+-/-2-benz21-2-/~3'-dimeth~lamAino-2'-meth~l-prop~ ~ ane A solution of 24.4 g /0.1 mole/ of /~/-2-benzyl-1,7,7-trimethyl-bicyclo/2.2,1/ heptan-2-ol in 100 ml o~ anhydrous toluene is added dropwise, under stirring, to a suspension of 2,4 g /0.1 mole/ o~ sodium hydride in 100 ml o~ anhydrous toluene. ~he reaction mixture is kept at 130 C ~or two hours, then a solution of 16,5 g /0.11 moles/ o~ l-dimethyl-amino-3-chloro-2-methyl-propane in 20 ml of anhydrous toluene ~ 55~1S
is added, and the mixture is allowed to stand at 130 C
~or further 8 hours. ~he mixture is cooled and shaken with a solution o~ 16.5 g /0.11 moles/ of tartaric acid in 80 ml o~ water. ~he aque~us phase is made alkaline to pH 10 with
~ 50 Therapeutic index =
The antiepileptic effect was investigated on white mice, after oral administration. The inhibition o~ maximal f ' I
~ ..
~ ~55~15 electroshock /MES/ was determined by the method o~ Swinyard et al. /~Swinyard et al. J. Pharmacol. E~p. ~her. 106, 319-330 /1952/ 7, White mice weighing 20-25 g were subjected to electric shock through corneal electr~s /Parameters:
50 Hz, 45 mA, 0.4 sec./. ~he total i~hibition o~ the tonic extensor convulsion was considered as criterion o~ the antî-convul~ive e~ect. ~he test-substance had been orally administered one hour be~ore the electroshock. ~he inhi~ition of pentetrazole convulsion was determined on white mice by the modified method o~ ~anziger and Hane / ~anziger, R., Hane, L.D. Arch. Int. Pharmacodyn. 167, 245-249 /1967/ ~.
The results are given in ~able I~ ~hereio "~h. I-" staodo ior "therapeutical inde~n.
~able II
-- Inhibition o~
Compound ~E9 ~ on No. of Example ~D50 mg/kg ~-~Fb~ 5 Wt~ r-1 130 12,3 2 lZ0 14.2 88 19.3 20 ` 5 380 5.3 140 14.3 6 120 16.7 54 37.0 7 56 21.4 66 18.2 8 30 28.3 20 42.5 12 72 27.7 110 18.2 13 140 14.3 140 14.3 16 30 23.3 60 11,7 17 _ _ 60 16.3 22 - - 96 10.4 Trimethadion 4.90 4,3 400 5.3 ~,5,5-Trimethy1-2 4--oxazoli~inedione~
;,t' /Ptim~l/
,.
L5~ S
~he inhibition of nicotine-le-thality was determined on white mice by the method of Stone / Stone, C.A., Mecklenburg, K.L., ~orchiana, M.L., Arch. Int, Pharmacodyn. 117, 419 /1958/~7, One hour a~ter the oral administration of the test-substance 1.4 mg/kg nicotine were injected and the number of the animalæ which suffered from convulsions or died was registered. ~he result~ are given in ~able III.
Table III
.
Compound ED ~herapeutic ~o. of Example mg/5g indeg :
1 38 42.1 2 20 85,0 7 25 48.0 8 11 77.3 30.0 17 50 19.6 ~rihexyphenidyl 40 9.13 (a-Cyolohe~rl-a-phe~y~-l-; 20 -piperidine-propanol~
(Ar~ace) ~he effect on the inhibition of the orie~tal activity /inhibition of the motility/ wa~ inve~tigated on white mice in a Dew~ app~ratus applied with 8 canal~ by the method of ~orsy / ~or~y, J., Cs~nyi, E., ~azar, I., Arc. Int. Pharmaco-dyn. 124, 1-2 /1960/ 7. After an oral pretreatment of 30 minute~ the number o~ light-interruptions due to the movement~
of groups con~isting o~ 3-3 mice was regi~tered. ~he observation lasted ~or 30 minute~. ~he ef~ect o~ the compounds exerted ,~.
~155~1S
on the duration of hexobarbita~ narcosis was tested by the method of Kaergaard /~Kaergaard, N.C., Magnussen, M. P., Kampmann, E., ~rey, H.H., Arc. Int. Pharmacodyn. 2, 170 /1967/ 7. Groups of animals consisting of 6-6 mice were treated. 20 ml/kg of 0.9 % sodium chloride solution were administered to the animals of the control group, then 40 mg/kg o~ hexobarbital were injected, i,v. Those animals of the treated group were considered to be of a positive reaction which showed a sleeping period being at least 2,5 times longer then the sleeping period of the control group.
~he results are given in lable IV.
~able IV
Compound Inhibition of Potentiating of ~o, of Examplemotility narcosi~
ED50 mg/kg ~h.I.ED50 mg/kg Th.I
1 110 14~5 90 17.7 2 _ _ 15 113.3 7 go 13.3 3 - - 120 10.4 190 10.5 120 16,7 6 100 20.0 80 25.0 8 60 14.2 60 14.2 11 130 11.5 130 11.5 12 - _ 200 10.0 13 170 11.8 _ _ 14 38 26.3 64 15,6 - - 40 22.5 16 _ 20 35.0 19 - - 50 20.0 22 100 10.0 80 12.5 Meprobamate 270 4.1 250 4.4 ~r (2-~thyl-2-propyl--1,3-propanediol ?
.. . .
.
. . .. -.: . ... , ~ ;`;,... .
~55115 ~he compounds of the general formula /I/ and therapeutically acceptable acid addition salts and quaternary salts thereo~
ca~ be formulated with the use o~ additives and/or carriers and/or adjuvants generally u~ed in pharmacy, by standard techniques.
According to a ~urther ~eature of the present invention there are provided the above pharmaceutical compositions which can be formulated in solid /e.g. tablets, capsules, coated pills, etc./ or liquid /e.g. solutions, suspensions, emulsions, etc./ form. ~hese pharmaceutical compositions can be administered orally /e.g. tablets, coated pills, capsules, solutions, etc./, rectally /e.g. suppositories/, or parenterally /e.g. injections/, The carriers may be such generally used in pharmacy /e,g. starch, magnesium stearate, calcium carbonate, poly-vinylpyrrolidone, gelatine, lactose, glucose, water, etc./.
The compositions may also contain suitable additives /e.g.
emulsi~ying, suspensing, disintegrating agents, buf~ers, etc,/
~he daily oral dose of the compounds of the general formula /I/ amounts approximately to about 0.25-75 mg. ~hese values are, however, nearly of an in~ormative character and the actually applied dose depends on the circumstances of the given case and the prescription of the physiclan and may lay below or above the ~aid interval.
~he invention is illustrated by the following Examples of non-limiting character:
E:EamPle 1 Pre~aration o~ 2-benzyl-2-/3'-dimethylaminopropoxy/-1,7,7-trimethyl-bicyclo/2.2.1/ heptane ~rl llS5115 _ 14 --A suspension o~ 3.9 g /0.1 moleJ of sodium amide in 100 ml of anhydrous benzene is heated to boiling, and a solution of 24.4 g /0.1 mole/ of /~/-2-benzyl-1,7,7-trimethyl-bicyclo/2,2.1/-hept~ n-2-ol in 100 ml of anhydrous benzene is added dropwise, under continuous stirring. When the addition of the above solution is completed the reaction miæture is boiled until the formation of ammonia gas is ceased, and while further continuing the ætirring, a solution of 13.4 g /0.11 mole/ of 1-dimethylamino-3-chloro-propane in 20 ml of anhydrous benzene is added. After boiling the mixture for further 6 hours it is cooled to 30 C, washed three times with 40 ml of water each, and extracted with a solution of 15 g /0,1 mole/ o~ tartaric acid in 50 ml of water or with 0.11 mole of diluted aqueous hydrochloric acid. ~he aqu~us solution cooled to 0-5 C is made alkaline to pH 10 with concentrated ammonium hydroxide. ~he base separated as an oil is extracted with dichloroethane, On distilling o~f the solvant, the residue is fractionated in vacuo, Yield: 30.2 g /92 %/ of a pale yellow oil . p.: 140-146 C/26.7 Pa Pre~ar~tion of the hydro~en fumarate:
16.5 g /0.05 moles/ o~ the above base dissolved in 20 ml of acetone are added to a solution of 5~8 g /0.05 mole/
of fumaric acid in 60 ml of hot water. On cooling the reaction mixture the separated crystals are filtered off and dried.
Yield: 20.5 g /92 ~/
M.p,: 103-104 C
.~1 . ~
- .
r octanol K ~water ) - 6.4 = partition coef~icient Analysis for C26H39N05 /445.606/:
Calculated: C: 70.08 % ~: 8.82 % N: 3,14 %
~ound: C: 69.04 % ~: 9.02 % N: 3.09 %
Preparation of the hydrogen chloride:
A solution of 3.3 g /0.01 mole/ of the above base in 25 ml of anhydrous ethylacetate is acidi~ied to pH 5 with ethylacetate ~aturated with hydrochloric acid. The separated cr~stals are ~iltered o~f and dried, Yield: 3.5 g /95 %/
M.p.: 146-148 C
Analysis for C22H36ClN0 /365.99/:
Calculated: C: 72,19 % H: 9.90 % Cl: 9.69 N:3.83 %
~ound: C: 72.01 % H: 9,78 % Cl: 9.67 ~:3380 %
Prearation of the citrate:
A solution of 3.8 g /0.02 moles/ of citric acid in 30 ml o~ ethanol is added to a solution of 6.6 ~ tO.02 moles/
of the above base in 10 ml o~ acetone. The separated salt i~ ~iltered o~f and dried, Yield: 9.59 g /89 %/
M.p.: 131-133 C
Analysis for C28H45N2 /539 Calculated: C: 62.31 % H: 8.40 % N: 2.60 %
~ound: C: 62,13 % H: 8,27 % N: 2.68 %
Pre~aration of the tartarate:
A solution of 3.0 g /0.02 moles/ oftartaric acid in 30 ml o~ ethanol is added to a solution of 6.6 g /0.02 moles/
X , ,.
.
:;
~5~15 of the above b~æ ~ lOml of acetone. ~he separated salt is ~iltered o~f and dried.
Yield: 8.82 g /92 %/
M.p.: 92-94 C
Analysis ~or C26H41N07 /479,62/:
Calculated: C: 65.11 % H: 8.62 % N: 2,92 %
~ound: C: 65,37 % H: 8.73 % N: 2v87 %
Pre~aration of the iodometh~late:
A solution o~ 2.82 g /0.02 mol~ o~ methyl iodide in 50 ml o~ acetone is added to a solution of 6.6 g /0.02 mole/ o~ the above base in 50n~o~ acetone, then the reaction mixture is allowed to stand at room-temperature for a night.
~he separated salt is ~iltered o~ and dried.
Yield: 8.3 g /88 %/
M.p,: 187-189 C /decomp./
Analysis for C23H38IN0 /471.48/:
Calculated: C: 58,59 % H: 8.12 % I: 26.92 % N: 2.97 %
~ound: C 58.68 % H: 8.24 % I: 27.05 % N: 2.93 %
Examle 2 Pre~aration o~ ~+-/-2-benz21-2-/~3'-dimeth~lamAino-2'-meth~l-prop~ ~ ane A solution of 24.4 g /0.1 mole/ of /~/-2-benzyl-1,7,7-trimethyl-bicyclo/2.2,1/ heptan-2-ol in 100 ml o~ anhydrous toluene is added dropwise, under stirring, to a suspension of 2,4 g /0.1 mole/ o~ sodium hydride in 100 ml o~ anhydrous toluene. ~he reaction mixture is kept at 130 C ~or two hours, then a solution of 16,5 g /0.11 moles/ o~ l-dimethyl-amino-3-chloro-2-methyl-propane in 20 ml of anhydrous toluene ~ 55~1S
is added, and the mixture is allowed to stand at 130 C
~or further 8 hours. ~he mixture is cooled and shaken with a solution o~ 16.5 g /0.11 moles/ of tartaric acid in 80 ml o~ water. ~he aque~us phase is made alkaline to pH 10 with
5 concentrated ammonium hydroxide at 0-5 C and extracted with dichloroethane. The organic phase is separated, dried over anhydrous magnesium sul~ate and evaporated. ~he residual base can be used for salt ~ormation without distillation.
Yield: 31 g /90 ~0/
Hydrogen ~umarate, m,p,: 140-146 C
Analysis for C27H41N05 /459.633/:
Calculated: C: 70.55 % H: 8.99 ~0 N: 3.04 %
~ound: C: 71.02 % H: 8.90 % N: 3.01 %
~;~ 15 Examle 3 Pre~aration of /~/-2-benzYl-2-/2~-diisopro~ylaminoethog~/
. ~
1.7.7-trimethyl-bicyclo/2,2.1/ hetane On starting from 3.9 g /0.1 mole/ o~ sodium amide, 24.4 g /0~1 mole/ of /~/-2-benzyl-1,7,7-trimethyl-bicyclo-` 20 /2.2.1/ heptan- 2-ol and 18,0 g /0.11 moles/ of l-diiso-propylamino-2-chloro-ethane, one proceeds in the way as pecified in Example 1.
Yield: 30 g /80.7 %/ o~ a pale yellow oil ~,p.: 190-191 C/133,3 Pa Hydrogen ~umarate, m.p.: 128-130 C
r ootanol ~
K~ water /= 1-15 A~alysis for C29H45N05 /487.687/:
Calculated: C: 71.42 % H: 9.3 % N: 2.87 ~0 3 ~ound: C: 71.9 % H: 9.33 % N: 2.89 %
~t~ i .
, -, :
.
.:
~155115 - 18 _ Exam~le 4 Pre~aration of /t/-2-benzyl-2-~ 1~-/4~-benzYlDiPerazin~l/
proox~7-1.7.7-trimeth~l-bicgclo/2.2,1/ hePtane On starting from 3,9 g /0.1 mole/ of sodium amide, 24.4 g /0.1 mole/ of /t/-2-benzyl-1,7,7-trimethyl-bicyclo-/2,2.1/heptan-2-ol and 27.8 g /0.11 mole/ of l-benzyl--4-/3'-chloro-propyl/-piperazine, one proceeds in the way specified in Example 2.
Yield: 38 g /82.6 %/ of a yellow viscous oil.
Dihydrogen fumarate, m.p.: 207-209.55 C
Analysis for C39H52N209 /692,861/:
Calculated: C: 67.6 % H: 7.57 % N: 4.03 %
~ound: C: 67.25 ~0 H: 7.68 % N: 4.04 %
E~am~le 5 PreDaration o~ 2-benzYl-2-/3'-diiso~ro~lamino~ro~ox~/-7~7-trimeth~rl-bicYclo/2,2.1/he~tane On starting from 2.4 g /0.1 mole/ of sodium hydride, 24~4 e /o.l mole/ of /~/-2-benzyl-1,7,7-trimethyl-bicyclo--/2.2.1/heptan-2-ol and 19.55 g /0.11 moles/ of l-diiso-.~
propylamino-3-¢hloro-propane, one proceeds in the way as ~pecified in Example 2, Yield: 36.05 g /93.5 %/
Hydrogen ~umarate, m,p,: 93-95 C
Analysi~ for C30H47N05 /501.714/:
CQ1CU1Qted: C: 71.82 ~0 H: 9.44 % N: 2.79 %
Found: C: 71.50 % H: 9.61 % ~: 2.69 %
.' , ' ' ` .' .
~S5115 Example 6 Prearation of /+/-2-benzyl-2-/3'-diethylaminoProPoxy/-1,7.7-trimethyl-bicyclo~2,2.1/he~tane On starting ~om 2.4 g /0.1 mole/ o~ sodium hydride, 24.4 g /0.1 mole/ o~ 2-benzyl-1,7,7-trimethyl-bicyclo--/2~2.1/heptan-2 -ol and 16.46 g /0.11 moles/ o~ l-diethyl-amino-3-chloro-propane, one proceeds in the way as specified in Example 2.
Yield: 33 g /92.4 %/
Hydrogen ~umarate, m.p,: 123.5-125.5 C
Analysis or C28H43~05 /473.66/:
Calculated: C: 71.00 % H: 9.15 % ~: 2.96 %
~ound: C: 71.40 % H: 9.06 % N: 2.98 %
Eæam~le 7 Pre~aration of D_/_/_2_benzyl_2 /3'-dimethylamino~ro~oxy!--1.7.7-trimethyl-bicyclo/2.2,1/he~tane On starting ~rom 3.9 g /0.1 mole/ o~ sodium amide, 24.4 g /0.1 mole/ of D_/+/-2-benzyl-1,7,7-trimethyl-bicyclo-j2.2.1/heptan-2-ol t/ ~ 7DO = ~13,72; c=2, ethanol), and 13.4 g /0.11 moles/ of 1-dimethylamino-3-chloro-propane, one proceeds in the way as ~pecified in E 8 ple 1.
Yield: 30.87 g /93.7 %/ of a pale yellow oil .p.: 180-186 C/133.3 P~
~5 / ~ 720= -2.175 C /c=2; ethanol/
Hydrogen fumarate, m.p.: 144-146 C
~ octanol ~
K ~ water J 5-57 / 0~7D = -1.66 /c=2; ethanol/
_~q _ ~55~15 Analysis for C26H39N05 /445.606/:
Calculated: C: 70.08 % H: 8.82 % N: 3,14 %
~ound: C: 70.48 % H: 8.89 % N: 3,10 %
Example 8 Preparation_of D~ 2-benz~1-2-/2'-diethvlaminoethox~y~-1.7,7-trimet~y~ s~clo/2,2,1/he~tane On starting from 3.9 g /0.1 mole/ o~ sodium amide~
24,4 g /0, 1 mole/ o~ D-/~/_2-benzyl-1,7,7-trimethyl-bicyclo-/2,2,1/heptan-2-ol and 14,9 g /0,11 moles/ o~ l-diethyl-amino-2-chloro-ethane, one proceeds in the way as speci~ied in Example 1, Yield: 29,9 g /87 ~0/ o~ a pale yellow oil ~.p,: 157-163 C/53,3 Pa /~ 7DO- ~3,48 C /c=2, ethanol/
Hydrogen ~umarate, m,p,: 126,5-130,5 C
/ ot7D= +2,6 C /c=2, ethanol/
Analysis ~or C27H41N05 /459.633/:
Calculated: C: 70,55 % H: 8.99 % N: 3.05 %
~ound: C: 70,74 % H: 9.12 % N: 3,09 %
Exampl~_2 Preparation of /~-2-benzyl-2~ m~pholino-~ro~ox~ 7~7-trimet,y~ clo/2,2 l/he~tane On starting from 24,4 g /0.1 mole/ o~ /+/-2-benzyl-1,7,7-trimethyl-bicyclo/2,2,1/heptan- 2~ol and 18,0 g /0,11 moles/
o~ l-chloro-3-morpholino-propane, one proceeds in the way as speci~ied in Eæample 2, Yield: 30.57 g /82.3 %/
.~ ., ~5511S
_ 21 -Hydrogen *umarate, m.p.: 76-78 c Analysis 28 41 6 /4 7' Calculated: C: 68,96 % H: 8.48 % N: 2.87 %
~ound: C: 68.26 % x 8.4 % N: 2.84 %
5 ExamPle lo Preparation of /+/-2-/3 ~ -dimethylaminoproPoxy/-2-/*~ -methoxy-Phen~l/-1.7 7-trimethyl-bicyclo/2.2,1/he~tane On starting from 3.9 g /0.1 mole/ of sodium amide, 26.0 g /0.1 mole/ of /+/-2-/4'-methoxyphenyl/-1, 7, 7-trimethyl-bicyclo-/2,2.1/heptan-2-ol and 13.4 g /0.11 moles/ o~ l-dimethyl-amino-3-chloro-propane, one proceeds in the way as specifîed in Example 2.
Yield: 26.8 g /77.5 %/
Hydrogen fumarate, m~p.: 148-149 c Analysis for C26H39~6 /461-Calculated: C: 67.65 % H: 8.52 % ~: 3.03 %
~ound: C: 67.6 % H: 8.48 % ~: 3.00 %
ExamDle 11 PreDaration of /+/-2-/P-chloro-benz~l/-2-/3'-dimeth~lamino-~roDox~ .7,7-trimethyl-bioyclo/2,2.1/hetane On starting ~rom 3,9 g /0.1 mole/ o~ ~odium amide, 27.9 g /0.1 mole/ of /+/-2-/p-chloro-benzyl/-1,7,7-trimethyl-bicyclo-/2.2.1/heptan-2-ol and 14.4 g /o.ll moles/o~ l-dimethylamino-3-chloro-propane, one proceeds in the way as speci~ied in Example 1, Yield: 32,5 g /89,3 %/ of a pale yellow, viscous oil ~.p.: 171-173 c/46. 7 Pa Hgdrogen fumarate, m.p.: 145-146 C
~55115 octanol K ( water )= 3,64 Analysiæ for C26H38C1~05 /480.06/:
Calculated: ~: 65,05 % H:7,98 % Cl:7,39 % N:2,91 %
~ound: C: 64,9 % H:8,04 % Cl:7,24 % N:2,83 %
Exam~le 12 PreDaration of /~i-2-/~-chloro-benz~l/-2-/2'-dimethYlamin etho~y/-1.7,7-trimethyl-bicyclo/2,2,1/he~tane On starting from 3,9 g /0.1 mole/ of æodium amide, 27,9 g /0.1 mole/ of /~/-2-/p-chloro-benzyl/-1,7,7-trimet~yl-bioyclo/2.2.1/heptan-2-ol and 14,9 g /0.11 moleæ/ o~
l-diethylamino-2-chloro-ethane, one proceedæ in the way as speoi~ied in Example 1, Yield: 35,4 g /93,7 %/ of a pale yellow viæcous oil ~,p,: 162-167 C/26,7 Pa Hydrogen fumarate, m,p,: 110-112 C
octanol E~ 5.64 Analyæiæ ~or C27H40ClN05 /494,08/:
Calculated: C: 65,64 % H: 8.16 % Cl: 7.17 % N: 2,83 %
Found: C: 65,12 % H: 8.31 % Cl: 7.08 % ~: 2,77 %
ExamDle 13 Preparation oi /~/-2-~ /3'-dimethylamino-2'-meth~l/-DroDoxy7-2-/D-chloro-~henyl/-1~7,7-trimethyl-bioyclo/2,2,1/heDtane On starting from 3,9 g /0.1 mole/ o~ sodium amide, 26,5 g /0.1 mole/ o~ 2-/p-chloro-phenyl/-1,7,7-trimethyl-bicyclo/2,2,1/heptan- 2-ol and 16,5 g /0,11 mole/ of l-dimethylamino-2-methyl-3-chloro-propane, one proceedæ in the way as speci~ied in Example 1, Yield: 32,3 g /88,7 %/ o~ a pale yellow oil ~ ~ -~, .
i5~1S
P.p.: 154-158 C/26.7 Pa Hydrogen fumarate, m.p.: 159.5-162.5 C, ~octanol \
K ~water ~= 2-47 Analysis for C26H38ClN05 /480.06/:
Calculated: C~ 65.05 % H- 7.98 % C1: 7.38 % N: 2.91 %
~ound: C: 65.30 % H: 8.15 % Cl: 7.38 % N: 3,03 %
ExamDle 14 PreDaration of /+/-2-/3'-dimethylamino~roPoxy/-2-Dh-e~ 7-trimeth~l-bicyclo/2.2.1/he~tane On starting from 3.6 g /0~1 mole/ of sodium amide, 23.04 g /0.1 mole/ of /+/-2-phenyl-1,7,7-trimethyl-bicyclo/2,2.1/-heptan-2-ol and 13.4 g /0.11 moles/ of 1-dimethylamino-3-chloro-propane, one proceeds in the way as specified in Example 1.
Yield: 28,6 g /~0.64 %/ of a pale yellow oil .p.: 157-160 C/160 Pa Hydrogen fumarate, m,p.: 169,5-171.5 C
Analysis for C25H37N05 /431.58/:
Calculated: C: 69,58 % H: 8.64 % N: 3,24 %
~ound: C: 69.65 % H: 8.36 ~0 N: 3.18 %
ExamDle 1~5 Pre~aration o~ /~/-2-/2' ~ hen,Yl-1,7.7-trimeth~l-biay¢lo/2,2,1/hePtane 3,9 g /0.1 g atom/ of potassium metal are added to 100 ml of anhydrous xylene, and the mixture is reacted with 23.04 g /0.1 mole/ of /+/-2-phenyl-1,7,7-trimeth~l-bicyclo-/2,2,1/heptan- 2-ol under vigorous stirring, When the formation of hydrogen gas has ~eased, a solution of 10.3 g /0.11 moles/
~f l-dimethylamino-2-chloro-ethane in 30 ml of anhydrous xylene is introduced, under further stirring. The reaction X
~ 5 mixture is kept at 100 C for 6 hour~, then washedthrice with 50 ml o~ water, and extracted with a solution of 15 g /0.1 mole/ o* tartaric acid in 80 ml o~ water or with o.ll mole o~ diluted aqueous hydrochloric acid. The aqueous phase is made alkaline to pH 10 with an aqueous solution o~
potassium hydroxide of 20 % under cooling /at 0-5 C~.
The base separated as an oil is eætracted with ether, After distilling off the solvent the residue is either purified with fractionated distillation under vacuo or used for salt formation without any purification.
Yield: 25.2 g /83.6 ~0/ o~ a pale yellow oil B.p.: 131-135 C/26.7 Pa EIydrogen fumarate, m.p.: 180-182 C
Analy~is ~or C24H35N05 /417.55/:
Calculated: C: 69.03 % H: 8.45 % N: 3.35 %
Found: C~ 69.05 % H: 8.59 % N: 3.44 %
Example 16 Pre~aration of /+/-2-/3-diethYlaminopro~ox~/-2-phen~ 7 7 trime~ bic~clo/2.2.1/heptane On starting from 3.9 g /0.1 mole/ of æodium amide, 23.04 g /0.1 mole/ of /+/-2-phenyl-1,7,7-trimethyl-bicyclo-/2.2,1/heptan-2-ol and 16.46 ~ /0.11 mole~/ o~ l-diethyl-amino-3-ohloro-propane one proceeds in the way as specified in Example 1.
Yield: 23.5 g /68.4 ~0/
Hydrogen fum~rate, m.p.: 160-163 C
Analysis for C27H41~05 /459.63/:
Calculated: C: 70.55 % H: 8.99 % N: 3.05 %
~ound: C: 70.58 % H: 8.95 % N: 3.05 %
~!
~S5~S
Examle 17 Preparation o~ 2,-/2'-diethylaminoethox~/-2-~2" -thien~
1~7,7-trimeth~yl-bic~clo/2.2~1/hetane On starting ~rom 3,9 g /0.1 mole/ o~ sodium amide, 23.6 g /0.1 mole/ of /~/-2-/2'-thienyl/-1,7,7-trimethyl-bicyclo/2,2,1/heptan _2-ol and 14,9 g /0,11 mole/ of l-diethylamino-2-chloro-ethane one proceeds in the way as specified in Example 2, Yield: 27,4 g /81,7 ~0/
Hydrogen fumarate, m,p,: 132,5-135,5 C
~octanol ~
K~ ~ater t= 1.19 Y 24 37 5 /451,61/:
Calculated: C: 63,83 % H: 8,25 % N: 3,10 % S: 7,10 %
~ound: C: 64,10 % H: 8.27 % N: 3,15 % S: 7,05 %
Eæam~le 18 Pr-eparation o~ /+/-2-/~'-dimethylamino~rooxy/-2-/2"-thie~vl/-1~?1l_trimeth.vl-bic~olo/2,2,1/he~tane On starting ~rom 3,9 g /0.1 mole/ o~ sodium amide, 23,6 g /0,1 mole/ o~ /+/-2-/2'-thienyl/-1,7,7-trimethyl-bicyclo/2.2,1/heptan-2-ol and 13,4 g /0.11 mole~/ o~
l-dimethylamino-3-chloro-propane, one proceeds i~ the ~y as specified in Example 2, Yield: 30.7 g /95,6 %/
Hydrogen ~umarate, m.p,: 147-149 C
~ octanol \
K ~ water /- 1,12 Y 23 3s~0sS /437,61/
Calculated: C: 63,13 % H: 8,06 % N: 3,20 % S: 7,32 %
~ound: C: 63~45 % H: 8.20 % N: 3,14 % S: 7,36 %
~ 26 -Examp_e 19 Pre~aration of /+~-2~ diethylaminoProPox~-2-/2" -thienYl/-1,7 7-trimethyl-bicyclo/2, ? l/hePtane On starting ~rom 3,9 g /0.1 mole/ of sodium amide, 23.6 g /0.1 mole/ of /+/-2-/2'-thienyl/-1,7,7-trimethyl-bicyclo/2.2.1/-heptan- 2-ol and 16.46 g /0.11 moles/ of 1-diethylamino-3 chloro-propane, one proceeds in the way as specified in Example 2.
Yield: 32.4 g /96.6 %/
Hydrogen fumarate, m.p,: 113-115 C
Analysis for C25H33N05S /465.66/:
Calculated: C: 64,48 % H: 8.44 % N: 3.01 % S: 6,88 %
~ound: C: 64.25 % H: 8.64 % N: 3.04 % S: 6,80 %
Examle 20 Pre~aration of ~ 2-dimeth~laminoethoxy-2-hen~1-1~7.7-trimeth~l-bicyclo/2.2.1/hetane Into a flask equipped with a stirrer and filled with nitrogen there are weighed 60 ml of anhydrous ether and 3.3 g of lithium metal cut in small pieces. A~ter starting the stirrer 1-2 ml from 31,3 g /0.2 mole/ of bromobenzene are added. lhe further amount of bromobenzene is diluted with 60 ml of anhydrous ether and added to the reaction mixtureeo t~at it ghould keep boiling. W~len the total amount of bromo-benzene is added the mixture is kept boiling for an hour, then cooled to room temperature and the exceæs of lithium is filtered of~, ~hereafter the solution is reacted with a solution of 27.4 g /0.18 moles/ of J+/-1,7,7-trimethyl-bicyclo/2.2.1/heptane in 50 ml of anhydrous ether under stirring, and the mi~ture is kept boiling for two hours.
~hen a solution of 18.54 g /0.198 moles/ of l-dimethylamino-, ~, ~1~5~15 - 27 ~
2-chloro-ethane in 20 ml o~ anhydrous ether is added, ~fter refluxing ~or a few hours the reaction is completed, ~he mixture is cooled to room -temperature and washed several times with water u~il neutral. ~hen a solution of 20,88 g /0,18 mole~ of fumaric acid in 200 ml of water is added, and the mixture is stirred ~or t~o ho~rs, The crystals are filtered off and dried, Yield: 68,9 g /91,7 %/ of /+/~2-dimethylaminoetho~y-2-phenyl-1,7,7-trimethyl-bicyclo/2,2,1/heptane hydrogen fumarate M,p~: 180-182 C
Analysis for C24H35N05 /417,55/:
Calculated: C: 69,03 % H: 8,45 % N: 3,35 %
~ound: C: 68.93 % H: 8~40 % N: 3,27 %
Exam~le 21 Pre~aration of /+/-2-be~zYl-2-~ 3'-/N-cyclohexyl-N-methyl/-amino-~roPoxy7-1~7~7-trimethyl-bicyclo/2~2~l/he~tane .
On starting from 2,4 g /0,1 mole/ of sodium hydride, 24,4 g /0,1 mole/ of /+/-2-benzyl-1,7~7-trimethyl-bicyclo-/2,2,1/heptane-2-ol, 41,5 g /0,11 moles/ of 1-/N-cyclohexyl-N-methyl/amino-3-chloropropane, 140 ml of anhydrou~ -toluene and 64 ml of anhydrous dimethylformamide, the reaction is effected at 80 C in the way as specified in Example 2, Yield: 37,56 g /94,7 ~0/
Hydrogen fumarate, m,p,: 186 C /decomp,/
Analysis for C31X47N05 /513.73/:
Calculated: C: 72,48 % H: 9,22 % N: 2,73 %
~ound: C: 72,50 % H: 9,31 % N: 2,70 %
.
~155115 - 28 _ Exam~le 22 Prearation o~ 2-/P-me-thoxy~henyl/-2-/3'-dimethylamino-propoxy/-l~7~7-trimethyl-bicyclo/2.2~l/he~tan-e a./ 4,8 g /0.2 g atom/ o~ granulated magnesium metal are added to a solution o~ 37,4 g /0.2 moles/ o~ 4-bromo-anisole, ~he Grignard-reagent thus-obtained is reacted with a solution o~ 30 g /0.2 moles/ of /~/-1,7,7-tri-me-thyl-bicyclo/2.2,1/heptan-2-~ in 20 ml of anhydrous ether, After refluxing for a few hours the Grignard complex is decomposed with a solution of 24 g o~ ammonium chloride in 80 ml of ice-cold water, The ether phase is separated, dried over magnesium ~sul~ate and made free o~ solvent in vacuo, lhe residue of the evaporation is purified by fractionated distillation in vacuo, Yield: 43,9 g /84,4 %/ o~ a colourless viscous oil ~.p,: 155-165 C/173 Pa b,/ On starting ~rom a 50 % suspension of 7,8 g /0,1 mole/ of sodium amide in benzene, 26,03 g /0,1 mole/ o~ /~/-2-/p-methoxyphenyl/-1,7,7-trimethyl-bicyclo/2,2,1/heptan_ 2-ol and 13,4 g /0.11 moles/ of l-dimethylamino-3-chloropropane, one proceeds in the way as ~peci~ied in Example 1, Yield: 29,7 g /85,96 ~0/ o~ a pale yellow viscous oil Hydrogen ~umarate, m,p,: 149-151 C
Analysis for C26H39N06 /461,6/:
Calculated: C: 67.65 % H: 8,52 % N: 3.03 %
~ound: C: 68.01 % H: 8,61 % N: 3,11 %
.~
- 29 _ Example 23 Tablets containing 25 m~ of /+/-2-benz~1-2-/3'-diethylamino-pro~ox~/-1.7~7-trimethyl-bicyclo/2~2~l/heptane h~dro~en fumarate The composition of a tablet is as follows:
Active ingredient:25.0 mg Maize starch: 97.0 mg Polivinyl pyrroIidone:175.0 mg Magnesium stearate:3.0 m~
300.0 mg A mixture of the active ingredient and the maize starch is moistened with 10-15 % aqueous polivinyl pyrrolidone, then granulated and dried at 40-45 C. After repeated dryinæ
the granulate is mixed with the magnesium stearate and pressed into tablets weighing 300 mg, Exam~le 24 Dragées containin~ 25 m~ o~ /+/-2-benzyl-2-~ 3'-/dimeth~l-amino/-2'-methyl-propox~7-1.7~7-trimethyl-bic~clo/2.2.1/-he~tane h~dro~en ~umarate ~he composition of a dragée kernel is as ~ollows:
Active ingredient:25.0 mg Maize starch: 245,0 mg Gelatine: 8,0 mg ~alc: 18.0 mg Magnesium stearate:4,0~5 300.0 mg A mixture of the active ingredient and the maize starch is moistened with a 10 % aqueous gelatine solution, then granulated by passing through a sieve and dried at 40-45 C.
~he dry granulate is repeatedly sieved, homogenized with X
_ ~5~5 - 30 _ the talc and the magnesium stearate, ~inally compressed to dragée kernels of 300 mg each, ExamPle 25 Dra~ées containing 50 m~ o~ D-/+/-?-benz~1-2-/2'-dieth~l-aminoethoxy/-1,7.7-trime ~ 2,2,1/hevtane hydrogen ~umarate ~he composition of a dragée kernel is as follows:
Active ingredient:50.0 mg ~actose: 97,0 mg 10 Polivinyl pyrrolidone2,0 mg Magnesium stearate1,O m~
150.0 mg ~he granulate is prepared as in the foregoing Example, ~he weight of a dragée kernel is equal to 150 mg, ~he dragée kernels are coated in a manner known E~E se, by a layer consis-ting o~ sugar and talc, ~he finished dragée is coloured with a suitable non-toxic food pigment and polished with beewax, Exam~le 26 Gelatine casules containing 25 m~ o~ active ingredient ~he compo~ltion of a ~elatine capsule is as follow~:
Active ingredient:25,0 mg Maize starch: 265,0 mg 25 Aerosil: 6,0 mg Magnesium stearate: 4"0 300~0 mg ~he components are homogenized and then filled into gelatine capsules of an adequate size, F~1 ~5 Exam~le 27 In~ectable solution containing 25 mg o~ active substance An ampoule contains 25.0 mg of the ac-tive ingredient in 5 ml of twice distilled water, ~.
S511~i 2-Benzyl-2-( 2'-heY~amethylene-imino-ethoxy)~
-1,7,7-trimethyl-bicyclor2,2.1] heptane Starting from 5.85 g ( 1.5 mole~ of sodium-amide, 36.6 g ( 0.15 moles) of ( ~)-2-benzyl-1,7,7-trimethyl-bi-cyclor2.2.1] heptane-2-ol and 28.46 g ( 0.176 mole s) of 2-hexamethylene-imino-ethyl-chloride one proceed3 according to E~ample 1.
Yield: 48 g t 86.7 ,'0) lo Hydrogen fumarate, m.p.: 164-167 C; [~]DO= ~2.47 ( C=l; EtOH) Analysis for the formula C29H43N05 ( 45~.67):
calculated: C: 71.72 % H: 8.92 ~70 N: 2.88 %
found:C: 71.7 50 H: 9.0 % N: 2.9 %
~ - 32 -
Yield: 31 g /90 ~0/
Hydrogen ~umarate, m,p,: 140-146 C
Analysis for C27H41N05 /459.633/:
Calculated: C: 70.55 % H: 8.99 ~0 N: 3.04 %
~ound: C: 71.02 % H: 8.90 % N: 3.01 %
~;~ 15 Examle 3 Pre~aration of /~/-2-benzYl-2-/2~-diisopro~ylaminoethog~/
. ~
1.7.7-trimethyl-bicyclo/2,2.1/ hetane On starting from 3.9 g /0.1 mole/ o~ sodium amide, 24.4 g /0~1 mole/ of /~/-2-benzyl-1,7,7-trimethyl-bicyclo-` 20 /2.2.1/ heptan- 2-ol and 18,0 g /0.11 moles/ of l-diiso-propylamino-2-chloro-ethane, one proceeds in the way as pecified in Example 1.
Yield: 30 g /80.7 %/ o~ a pale yellow oil ~,p.: 190-191 C/133,3 Pa Hydrogen ~umarate, m.p.: 128-130 C
r ootanol ~
K~ water /= 1-15 A~alysis for C29H45N05 /487.687/:
Calculated: C: 71.42 % H: 9.3 % N: 2.87 ~0 3 ~ound: C: 71.9 % H: 9.33 % N: 2.89 %
~t~ i .
, -, :
.
.:
~155115 - 18 _ Exam~le 4 Pre~aration of /t/-2-benzyl-2-~ 1~-/4~-benzYlDiPerazin~l/
proox~7-1.7.7-trimeth~l-bicgclo/2.2,1/ hePtane On starting from 3,9 g /0.1 mole/ of sodium amide, 24.4 g /0.1 mole/ of /t/-2-benzyl-1,7,7-trimethyl-bicyclo-/2,2.1/heptan-2-ol and 27.8 g /0.11 mole/ of l-benzyl--4-/3'-chloro-propyl/-piperazine, one proceeds in the way specified in Example 2.
Yield: 38 g /82.6 %/ of a yellow viscous oil.
Dihydrogen fumarate, m.p.: 207-209.55 C
Analysis for C39H52N209 /692,861/:
Calculated: C: 67.6 % H: 7.57 % N: 4.03 %
~ound: C: 67.25 ~0 H: 7.68 % N: 4.04 %
E~am~le 5 PreDaration o~ 2-benzYl-2-/3'-diiso~ro~lamino~ro~ox~/-7~7-trimeth~rl-bicYclo/2,2.1/he~tane On starting from 2.4 g /0.1 mole/ of sodium hydride, 24~4 e /o.l mole/ of /~/-2-benzyl-1,7,7-trimethyl-bicyclo--/2.2.1/heptan-2-ol and 19.55 g /0.11 moles/ of l-diiso-.~
propylamino-3-¢hloro-propane, one proceeds in the way as ~pecified in Example 2, Yield: 36.05 g /93.5 %/
Hydrogen ~umarate, m,p,: 93-95 C
Analysi~ for C30H47N05 /501.714/:
CQ1CU1Qted: C: 71.82 ~0 H: 9.44 % N: 2.79 %
Found: C: 71.50 % H: 9.61 % ~: 2.69 %
.' , ' ' ` .' .
~S5115 Example 6 Prearation of /+/-2-benzyl-2-/3'-diethylaminoProPoxy/-1,7.7-trimethyl-bicyclo~2,2.1/he~tane On starting ~om 2.4 g /0.1 mole/ o~ sodium hydride, 24.4 g /0.1 mole/ o~ 2-benzyl-1,7,7-trimethyl-bicyclo--/2~2.1/heptan-2 -ol and 16.46 g /0.11 moles/ o~ l-diethyl-amino-3-chloro-propane, one proceeds in the way as specified in Example 2.
Yield: 33 g /92.4 %/
Hydrogen ~umarate, m.p,: 123.5-125.5 C
Analysis or C28H43~05 /473.66/:
Calculated: C: 71.00 % H: 9.15 % ~: 2.96 %
~ound: C: 71.40 % H: 9.06 % N: 2.98 %
Eæam~le 7 Pre~aration of D_/_/_2_benzyl_2 /3'-dimethylamino~ro~oxy!--1.7.7-trimethyl-bicyclo/2.2,1/he~tane On starting ~rom 3.9 g /0.1 mole/ o~ sodium amide, 24.4 g /0.1 mole/ of D_/+/-2-benzyl-1,7,7-trimethyl-bicyclo-j2.2.1/heptan-2-ol t/ ~ 7DO = ~13,72; c=2, ethanol), and 13.4 g /0.11 moles/ of 1-dimethylamino-3-chloro-propane, one proceeds in the way as ~pecified in E 8 ple 1.
Yield: 30.87 g /93.7 %/ of a pale yellow oil .p.: 180-186 C/133.3 P~
~5 / ~ 720= -2.175 C /c=2; ethanol/
Hydrogen fumarate, m.p.: 144-146 C
~ octanol ~
K ~ water J 5-57 / 0~7D = -1.66 /c=2; ethanol/
_~q _ ~55~15 Analysis for C26H39N05 /445.606/:
Calculated: C: 70.08 % H: 8.82 % N: 3,14 %
~ound: C: 70.48 % H: 8.89 % N: 3,10 %
Example 8 Preparation_of D~ 2-benz~1-2-/2'-diethvlaminoethox~y~-1.7,7-trimet~y~ s~clo/2,2,1/he~tane On starting from 3.9 g /0.1 mole/ o~ sodium amide~
24,4 g /0, 1 mole/ o~ D-/~/_2-benzyl-1,7,7-trimethyl-bicyclo-/2,2,1/heptan-2-ol and 14,9 g /0,11 moles/ o~ l-diethyl-amino-2-chloro-ethane, one proceeds in the way as speci~ied in Example 1, Yield: 29,9 g /87 ~0/ o~ a pale yellow oil ~.p,: 157-163 C/53,3 Pa /~ 7DO- ~3,48 C /c=2, ethanol/
Hydrogen ~umarate, m,p,: 126,5-130,5 C
/ ot7D= +2,6 C /c=2, ethanol/
Analysis ~or C27H41N05 /459.633/:
Calculated: C: 70,55 % H: 8.99 % N: 3.05 %
~ound: C: 70,74 % H: 9.12 % N: 3,09 %
Exampl~_2 Preparation of /~-2-benzyl-2~ m~pholino-~ro~ox~ 7~7-trimet,y~ clo/2,2 l/he~tane On starting from 24,4 g /0.1 mole/ o~ /+/-2-benzyl-1,7,7-trimethyl-bicyclo/2,2,1/heptan- 2~ol and 18,0 g /0,11 moles/
o~ l-chloro-3-morpholino-propane, one proceeds in the way as speci~ied in Eæample 2, Yield: 30.57 g /82.3 %/
.~ ., ~5511S
_ 21 -Hydrogen *umarate, m.p.: 76-78 c Analysis 28 41 6 /4 7' Calculated: C: 68,96 % H: 8.48 % N: 2.87 %
~ound: C: 68.26 % x 8.4 % N: 2.84 %
5 ExamPle lo Preparation of /+/-2-/3 ~ -dimethylaminoproPoxy/-2-/*~ -methoxy-Phen~l/-1.7 7-trimethyl-bicyclo/2.2,1/he~tane On starting from 3.9 g /0.1 mole/ of sodium amide, 26.0 g /0.1 mole/ of /+/-2-/4'-methoxyphenyl/-1, 7, 7-trimethyl-bicyclo-/2,2.1/heptan-2-ol and 13.4 g /0.11 moles/ o~ l-dimethyl-amino-3-chloro-propane, one proceeds in the way as specifîed in Example 2.
Yield: 26.8 g /77.5 %/
Hydrogen fumarate, m~p.: 148-149 c Analysis for C26H39~6 /461-Calculated: C: 67.65 % H: 8.52 % ~: 3.03 %
~ound: C: 67.6 % H: 8.48 % ~: 3.00 %
ExamDle 11 PreDaration of /+/-2-/P-chloro-benz~l/-2-/3'-dimeth~lamino-~roDox~ .7,7-trimethyl-bioyclo/2,2.1/hetane On starting ~rom 3,9 g /0.1 mole/ o~ ~odium amide, 27.9 g /0.1 mole/ of /+/-2-/p-chloro-benzyl/-1,7,7-trimethyl-bicyclo-/2.2.1/heptan-2-ol and 14.4 g /o.ll moles/o~ l-dimethylamino-3-chloro-propane, one proceeds in the way as speci~ied in Example 1, Yield: 32,5 g /89,3 %/ of a pale yellow, viscous oil ~.p.: 171-173 c/46. 7 Pa Hgdrogen fumarate, m.p.: 145-146 C
~55115 octanol K ( water )= 3,64 Analysiæ for C26H38C1~05 /480.06/:
Calculated: ~: 65,05 % H:7,98 % Cl:7,39 % N:2,91 %
~ound: C: 64,9 % H:8,04 % Cl:7,24 % N:2,83 %
Exam~le 12 PreDaration of /~i-2-/~-chloro-benz~l/-2-/2'-dimethYlamin etho~y/-1.7,7-trimethyl-bicyclo/2,2,1/he~tane On starting from 3,9 g /0.1 mole/ of æodium amide, 27,9 g /0.1 mole/ of /~/-2-/p-chloro-benzyl/-1,7,7-trimet~yl-bioyclo/2.2.1/heptan-2-ol and 14,9 g /0.11 moleæ/ o~
l-diethylamino-2-chloro-ethane, one proceedæ in the way as speoi~ied in Example 1, Yield: 35,4 g /93,7 %/ of a pale yellow viæcous oil ~,p,: 162-167 C/26,7 Pa Hydrogen fumarate, m,p,: 110-112 C
octanol E~ 5.64 Analyæiæ ~or C27H40ClN05 /494,08/:
Calculated: C: 65,64 % H: 8.16 % Cl: 7.17 % N: 2,83 %
Found: C: 65,12 % H: 8.31 % Cl: 7.08 % ~: 2,77 %
ExamDle 13 Preparation oi /~/-2-~ /3'-dimethylamino-2'-meth~l/-DroDoxy7-2-/D-chloro-~henyl/-1~7,7-trimethyl-bioyclo/2,2,1/heDtane On starting from 3,9 g /0.1 mole/ o~ sodium amide, 26,5 g /0.1 mole/ o~ 2-/p-chloro-phenyl/-1,7,7-trimethyl-bicyclo/2,2,1/heptan- 2-ol and 16,5 g /0,11 mole/ of l-dimethylamino-2-methyl-3-chloro-propane, one proceedæ in the way as speci~ied in Example 1, Yield: 32,3 g /88,7 %/ o~ a pale yellow oil ~ ~ -~, .
i5~1S
P.p.: 154-158 C/26.7 Pa Hydrogen fumarate, m.p.: 159.5-162.5 C, ~octanol \
K ~water ~= 2-47 Analysis for C26H38ClN05 /480.06/:
Calculated: C~ 65.05 % H- 7.98 % C1: 7.38 % N: 2.91 %
~ound: C: 65.30 % H: 8.15 % Cl: 7.38 % N: 3,03 %
ExamDle 14 PreDaration of /+/-2-/3'-dimethylamino~roPoxy/-2-Dh-e~ 7-trimeth~l-bicyclo/2.2.1/he~tane On starting from 3.6 g /0~1 mole/ of sodium amide, 23.04 g /0.1 mole/ of /+/-2-phenyl-1,7,7-trimethyl-bicyclo/2,2.1/-heptan-2-ol and 13.4 g /0.11 moles/ of 1-dimethylamino-3-chloro-propane, one proceeds in the way as specified in Example 1.
Yield: 28,6 g /~0.64 %/ of a pale yellow oil .p.: 157-160 C/160 Pa Hydrogen fumarate, m,p.: 169,5-171.5 C
Analysis for C25H37N05 /431.58/:
Calculated: C: 69,58 % H: 8.64 % N: 3,24 %
~ound: C: 69.65 % H: 8.36 ~0 N: 3.18 %
ExamDle 1~5 Pre~aration o~ /~/-2-/2' ~ hen,Yl-1,7.7-trimeth~l-biay¢lo/2,2,1/hePtane 3,9 g /0.1 g atom/ of potassium metal are added to 100 ml of anhydrous xylene, and the mixture is reacted with 23.04 g /0.1 mole/ of /+/-2-phenyl-1,7,7-trimeth~l-bicyclo-/2,2,1/heptan- 2-ol under vigorous stirring, When the formation of hydrogen gas has ~eased, a solution of 10.3 g /0.11 moles/
~f l-dimethylamino-2-chloro-ethane in 30 ml of anhydrous xylene is introduced, under further stirring. The reaction X
~ 5 mixture is kept at 100 C for 6 hour~, then washedthrice with 50 ml o~ water, and extracted with a solution of 15 g /0.1 mole/ o* tartaric acid in 80 ml o~ water or with o.ll mole o~ diluted aqueous hydrochloric acid. The aqueous phase is made alkaline to pH 10 with an aqueous solution o~
potassium hydroxide of 20 % under cooling /at 0-5 C~.
The base separated as an oil is eætracted with ether, After distilling off the solvent the residue is either purified with fractionated distillation under vacuo or used for salt formation without any purification.
Yield: 25.2 g /83.6 ~0/ o~ a pale yellow oil B.p.: 131-135 C/26.7 Pa EIydrogen fumarate, m.p.: 180-182 C
Analy~is ~or C24H35N05 /417.55/:
Calculated: C: 69.03 % H: 8.45 % N: 3.35 %
Found: C~ 69.05 % H: 8.59 % N: 3.44 %
Example 16 Pre~aration of /+/-2-/3-diethYlaminopro~ox~/-2-phen~ 7 7 trime~ bic~clo/2.2.1/heptane On starting from 3.9 g /0.1 mole/ of æodium amide, 23.04 g /0.1 mole/ of /+/-2-phenyl-1,7,7-trimethyl-bicyclo-/2.2,1/heptan-2-ol and 16.46 ~ /0.11 mole~/ o~ l-diethyl-amino-3-ohloro-propane one proceeds in the way as specified in Example 1.
Yield: 23.5 g /68.4 ~0/
Hydrogen fum~rate, m.p.: 160-163 C
Analysis for C27H41~05 /459.63/:
Calculated: C: 70.55 % H: 8.99 % N: 3.05 %
~ound: C: 70.58 % H: 8.95 % N: 3.05 %
~!
~S5~S
Examle 17 Preparation o~ 2,-/2'-diethylaminoethox~/-2-~2" -thien~
1~7,7-trimeth~yl-bic~clo/2.2~1/hetane On starting ~rom 3,9 g /0.1 mole/ o~ sodium amide, 23.6 g /0.1 mole/ of /~/-2-/2'-thienyl/-1,7,7-trimethyl-bicyclo/2,2,1/heptan _2-ol and 14,9 g /0,11 mole/ of l-diethylamino-2-chloro-ethane one proceeds in the way as specified in Example 2, Yield: 27,4 g /81,7 ~0/
Hydrogen fumarate, m,p,: 132,5-135,5 C
~octanol ~
K~ ~ater t= 1.19 Y 24 37 5 /451,61/:
Calculated: C: 63,83 % H: 8,25 % N: 3,10 % S: 7,10 %
~ound: C: 64,10 % H: 8.27 % N: 3,15 % S: 7,05 %
Eæam~le 18 Pr-eparation o~ /+/-2-/~'-dimethylamino~rooxy/-2-/2"-thie~vl/-1~?1l_trimeth.vl-bic~olo/2,2,1/he~tane On starting ~rom 3,9 g /0.1 mole/ o~ sodium amide, 23,6 g /0,1 mole/ o~ /+/-2-/2'-thienyl/-1,7,7-trimethyl-bicyclo/2.2,1/heptan-2-ol and 13,4 g /0.11 mole~/ o~
l-dimethylamino-3-chloro-propane, one proceeds i~ the ~y as specified in Example 2, Yield: 30.7 g /95,6 %/
Hydrogen ~umarate, m.p,: 147-149 C
~ octanol \
K ~ water /- 1,12 Y 23 3s~0sS /437,61/
Calculated: C: 63,13 % H: 8,06 % N: 3,20 % S: 7,32 %
~ound: C: 63~45 % H: 8.20 % N: 3,14 % S: 7,36 %
~ 26 -Examp_e 19 Pre~aration of /+~-2~ diethylaminoProPox~-2-/2" -thienYl/-1,7 7-trimethyl-bicyclo/2, ? l/hePtane On starting ~rom 3,9 g /0.1 mole/ of sodium amide, 23.6 g /0.1 mole/ of /+/-2-/2'-thienyl/-1,7,7-trimethyl-bicyclo/2.2.1/-heptan- 2-ol and 16.46 g /0.11 moles/ of 1-diethylamino-3 chloro-propane, one proceeds in the way as specified in Example 2.
Yield: 32.4 g /96.6 %/
Hydrogen fumarate, m.p,: 113-115 C
Analysis for C25H33N05S /465.66/:
Calculated: C: 64,48 % H: 8.44 % N: 3.01 % S: 6,88 %
~ound: C: 64.25 % H: 8.64 % N: 3.04 % S: 6,80 %
Examle 20 Pre~aration of ~ 2-dimeth~laminoethoxy-2-hen~1-1~7.7-trimeth~l-bicyclo/2.2.1/hetane Into a flask equipped with a stirrer and filled with nitrogen there are weighed 60 ml of anhydrous ether and 3.3 g of lithium metal cut in small pieces. A~ter starting the stirrer 1-2 ml from 31,3 g /0.2 mole/ of bromobenzene are added. lhe further amount of bromobenzene is diluted with 60 ml of anhydrous ether and added to the reaction mixtureeo t~at it ghould keep boiling. W~len the total amount of bromo-benzene is added the mixture is kept boiling for an hour, then cooled to room temperature and the exceæs of lithium is filtered of~, ~hereafter the solution is reacted with a solution of 27.4 g /0.18 moles/ of J+/-1,7,7-trimethyl-bicyclo/2.2.1/heptane in 50 ml of anhydrous ether under stirring, and the mi~ture is kept boiling for two hours.
~hen a solution of 18.54 g /0.198 moles/ of l-dimethylamino-, ~, ~1~5~15 - 27 ~
2-chloro-ethane in 20 ml o~ anhydrous ether is added, ~fter refluxing ~or a few hours the reaction is completed, ~he mixture is cooled to room -temperature and washed several times with water u~il neutral. ~hen a solution of 20,88 g /0,18 mole~ of fumaric acid in 200 ml of water is added, and the mixture is stirred ~or t~o ho~rs, The crystals are filtered off and dried, Yield: 68,9 g /91,7 %/ of /+/~2-dimethylaminoetho~y-2-phenyl-1,7,7-trimethyl-bicyclo/2,2,1/heptane hydrogen fumarate M,p~: 180-182 C
Analysis for C24H35N05 /417,55/:
Calculated: C: 69,03 % H: 8,45 % N: 3,35 %
~ound: C: 68.93 % H: 8~40 % N: 3,27 %
Exam~le 21 Pre~aration of /+/-2-be~zYl-2-~ 3'-/N-cyclohexyl-N-methyl/-amino-~roPoxy7-1~7~7-trimethyl-bicyclo/2~2~l/he~tane .
On starting from 2,4 g /0,1 mole/ of sodium hydride, 24,4 g /0,1 mole/ of /+/-2-benzyl-1,7~7-trimethyl-bicyclo-/2,2,1/heptane-2-ol, 41,5 g /0,11 moles/ of 1-/N-cyclohexyl-N-methyl/amino-3-chloropropane, 140 ml of anhydrou~ -toluene and 64 ml of anhydrous dimethylformamide, the reaction is effected at 80 C in the way as specified in Example 2, Yield: 37,56 g /94,7 ~0/
Hydrogen fumarate, m,p,: 186 C /decomp,/
Analysis for C31X47N05 /513.73/:
Calculated: C: 72,48 % H: 9,22 % N: 2,73 %
~ound: C: 72,50 % H: 9,31 % N: 2,70 %
.
~155115 - 28 _ Exam~le 22 Prearation o~ 2-/P-me-thoxy~henyl/-2-/3'-dimethylamino-propoxy/-l~7~7-trimethyl-bicyclo/2.2~l/he~tan-e a./ 4,8 g /0.2 g atom/ o~ granulated magnesium metal are added to a solution o~ 37,4 g /0.2 moles/ o~ 4-bromo-anisole, ~he Grignard-reagent thus-obtained is reacted with a solution o~ 30 g /0.2 moles/ of /~/-1,7,7-tri-me-thyl-bicyclo/2.2,1/heptan-2-~ in 20 ml of anhydrous ether, After refluxing for a few hours the Grignard complex is decomposed with a solution of 24 g o~ ammonium chloride in 80 ml of ice-cold water, The ether phase is separated, dried over magnesium ~sul~ate and made free o~ solvent in vacuo, lhe residue of the evaporation is purified by fractionated distillation in vacuo, Yield: 43,9 g /84,4 %/ o~ a colourless viscous oil ~.p,: 155-165 C/173 Pa b,/ On starting ~rom a 50 % suspension of 7,8 g /0,1 mole/ of sodium amide in benzene, 26,03 g /0,1 mole/ o~ /~/-2-/p-methoxyphenyl/-1,7,7-trimethyl-bicyclo/2,2,1/heptan_ 2-ol and 13,4 g /0.11 moles/ of l-dimethylamino-3-chloropropane, one proceeds in the way as ~peci~ied in Example 1, Yield: 29,7 g /85,96 ~0/ o~ a pale yellow viscous oil Hydrogen ~umarate, m,p,: 149-151 C
Analysis for C26H39N06 /461,6/:
Calculated: C: 67.65 % H: 8,52 % N: 3.03 %
~ound: C: 68.01 % H: 8,61 % N: 3,11 %
.~
- 29 _ Example 23 Tablets containing 25 m~ of /+/-2-benz~1-2-/3'-diethylamino-pro~ox~/-1.7~7-trimethyl-bicyclo/2~2~l/heptane h~dro~en fumarate The composition of a tablet is as follows:
Active ingredient:25.0 mg Maize starch: 97.0 mg Polivinyl pyrroIidone:175.0 mg Magnesium stearate:3.0 m~
300.0 mg A mixture of the active ingredient and the maize starch is moistened with 10-15 % aqueous polivinyl pyrrolidone, then granulated and dried at 40-45 C. After repeated dryinæ
the granulate is mixed with the magnesium stearate and pressed into tablets weighing 300 mg, Exam~le 24 Dragées containin~ 25 m~ o~ /+/-2-benzyl-2-~ 3'-/dimeth~l-amino/-2'-methyl-propox~7-1.7~7-trimethyl-bic~clo/2.2.1/-he~tane h~dro~en ~umarate ~he composition of a dragée kernel is as ~ollows:
Active ingredient:25.0 mg Maize starch: 245,0 mg Gelatine: 8,0 mg ~alc: 18.0 mg Magnesium stearate:4,0~5 300.0 mg A mixture of the active ingredient and the maize starch is moistened with a 10 % aqueous gelatine solution, then granulated by passing through a sieve and dried at 40-45 C.
~he dry granulate is repeatedly sieved, homogenized with X
_ ~5~5 - 30 _ the talc and the magnesium stearate, ~inally compressed to dragée kernels of 300 mg each, ExamPle 25 Dra~ées containing 50 m~ o~ D-/+/-?-benz~1-2-/2'-dieth~l-aminoethoxy/-1,7.7-trime ~ 2,2,1/hevtane hydrogen ~umarate ~he composition of a dragée kernel is as follows:
Active ingredient:50.0 mg ~actose: 97,0 mg 10 Polivinyl pyrrolidone2,0 mg Magnesium stearate1,O m~
150.0 mg ~he granulate is prepared as in the foregoing Example, ~he weight of a dragée kernel is equal to 150 mg, ~he dragée kernels are coated in a manner known E~E se, by a layer consis-ting o~ sugar and talc, ~he finished dragée is coloured with a suitable non-toxic food pigment and polished with beewax, Exam~le 26 Gelatine casules containing 25 m~ o~ active ingredient ~he compo~ltion of a ~elatine capsule is as follow~:
Active ingredient:25,0 mg Maize starch: 265,0 mg 25 Aerosil: 6,0 mg Magnesium stearate: 4"0 300~0 mg ~he components are homogenized and then filled into gelatine capsules of an adequate size, F~1 ~5 Exam~le 27 In~ectable solution containing 25 mg o~ active substance An ampoule contains 25.0 mg of the ac-tive ingredient in 5 ml of twice distilled water, ~.
S511~i 2-Benzyl-2-( 2'-heY~amethylene-imino-ethoxy)~
-1,7,7-trimethyl-bicyclor2,2.1] heptane Starting from 5.85 g ( 1.5 mole~ of sodium-amide, 36.6 g ( 0.15 moles) of ( ~)-2-benzyl-1,7,7-trimethyl-bi-cyclor2.2.1] heptane-2-ol and 28.46 g ( 0.176 mole s) of 2-hexamethylene-imino-ethyl-chloride one proceed3 according to E~ample 1.
Yield: 48 g t 86.7 ,'0) lo Hydrogen fumarate, m.p.: 164-167 C; [~]DO= ~2.47 ( C=l; EtOH) Analysis for the formula C29H43N05 ( 45~.67):
calculated: C: 71.72 % H: 8.92 ~70 N: 2.88 %
found:C: 71.7 50 H: 9.0 % N: 2.9 %
~ - 32 -
Claims (32)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a basic ether of the general formula I or a pharmaceutically acceptable acid addition salt or quaternary salt, thereof, I
wherein R1 and R2 may be the same or different and represent a C1-5 alkyl group or a C3-6 cycloalkyl group or they form, together with the adjacent nitrogen atom, a saturated 5-, 6- or 7-membered heterocyclic ring which optionally con-tains a further hetero atom which is an oxygen, sulfur or nitrogen atom; R repre-sents a phenyl, phenyl-(C1-3 alkyl) or thienyl group optionally substituted by one or more halogen or C1-3 alkoxy substituent(s); A represents a C2-5 straight or branched alkylene chain, and ? represents a valence bond of .alpha. or .beta. con-figuration, which process comprises (a) reacting a compound of the general formula II
II
R has the meaning given above, and R3 denotes an alkali metal atom, an alkaline-earth metal atom or a group of the general formula X-Me, wherein X denotes halogen and Me stands for alkaline-earth metal atom, with a compound of the general formula III
III
wherein Y stands for halogen and A, R1 and R2 have the meanings given above; or (b) treating a compound of the general formula IV
IV
wherein R has the meaning given above; with an agent for introducing an R3 group and the compound of the general formula II thus obtained, wherein R and R3 have the meanings given above, is reacted with a compound of the general formula III;
or (c) reacting 1,7,7-trimethyl-bicyclo[2.2.1]heptane-2-one with an organo-metallic compound, decomposing the obtained complex thus-obtained is decomposed, and reacting the obtained compound of the general formula IV, wherein R has the meaning given above, with a base for introducing an R3 group, reacting the obtained compound of the general formula II with a compound of the general formula III, and if required, converting the compound of the general formula I into a pharmaceutically acceptable acid addition salt or quaternary salt.
wherein R1 and R2 may be the same or different and represent a C1-5 alkyl group or a C3-6 cycloalkyl group or they form, together with the adjacent nitrogen atom, a saturated 5-, 6- or 7-membered heterocyclic ring which optionally con-tains a further hetero atom which is an oxygen, sulfur or nitrogen atom; R repre-sents a phenyl, phenyl-(C1-3 alkyl) or thienyl group optionally substituted by one or more halogen or C1-3 alkoxy substituent(s); A represents a C2-5 straight or branched alkylene chain, and ? represents a valence bond of .alpha. or .beta. con-figuration, which process comprises (a) reacting a compound of the general formula II
II
R has the meaning given above, and R3 denotes an alkali metal atom, an alkaline-earth metal atom or a group of the general formula X-Me, wherein X denotes halogen and Me stands for alkaline-earth metal atom, with a compound of the general formula III
III
wherein Y stands for halogen and A, R1 and R2 have the meanings given above; or (b) treating a compound of the general formula IV
IV
wherein R has the meaning given above; with an agent for introducing an R3 group and the compound of the general formula II thus obtained, wherein R and R3 have the meanings given above, is reacted with a compound of the general formula III;
or (c) reacting 1,7,7-trimethyl-bicyclo[2.2.1]heptane-2-one with an organo-metallic compound, decomposing the obtained complex thus-obtained is decomposed, and reacting the obtained compound of the general formula IV, wherein R has the meaning given above, with a base for introducing an R3 group, reacting the obtained compound of the general formula II with a compound of the general formula III, and if required, converting the compound of the general formula I into a pharmaceutically acceptable acid addition salt or quaternary salt.
2. A process as claimed in claim 1, wherein a compound of the general formula II, wherein R3 stands for a sodium or lithium atom is used as starting compound.
3. A process as claimed in claim 1, wherein an alkali metal hydride, an alkali metal amide, or an alkali metal, is used as an agent for introducing an R3 group.
4. A process as claimed in claim 1 wherein sodium, potassium, sodium hydride or sodium amide is used as an agent for introducing an R3 group.
5. A process as claimed in claim 1, 2 or 3 wherein the reaction is carried out at a temperature between -10°C and 200°C.
6. A process as claimed in claim 1, 2 or 3 wherein the reaction is carried out at a temperature between 10°C and 100°C.
7. A process as claimed in claim 1, wherein a sodium- or lithium-compound or a Grignard-reagent is used as organo-metallic compound.
8. A process as claimed in claim 1, wherein process (b) or (c) is used and the compound of general formula II is reacted with the compound of general formula III without isolation from the reaction mixture in which it is prepared.
9. A process as claimed in claim 1, wherein R1 and R2 each denote a methyl or ethyl group, R represents a phenyl, benzyl or C1-3-alkoxy-phenyl group and A is an ethylene, propylene or 2-methyl-propylene group.
10. A process as claimed in claim 1 wherein R1 and R2 are both C1-5 alkyl groups.
11. A compound of formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt or quaternary salt thereof when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.
12. A process as claimed in claim 1 wherein R is a benzyl group, A is a 2-methyl-propylene group and R1 and R2 are both methyl groups.
13. A process for preparing 2-benzyl-2-(3'-dimethylamino-2'-methyl-propoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane or its hydrogen fumarate salt which comprises reacting 2-benzyl-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-ol with sodium hydride followed by reaction with 1-dimethylamino-3-chloro-2-methyl-propane and, if the hydrogen fumarate, hydrochloride, citrate, tartrate or iodomethylate salt is required, reacting the product with fumaric acid.
14. The compound 2-benzyl-2-(3'-dimethylamino-2'-methyl-propoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane or its hydrogen fumarate salt when prepared by a process according to claim 13 or an obvious chemical equivalent thereof.
15. A process as claimed in claim 1 wherein R is a benzyl group, A is a propylene group and R1 and R1 are both ethyl groups.
16. A process for preparing 2-benzyl-2-(3'-diethylaminopropoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane or its hydrogen fumarate salt which comprises reacting 2-benzyl-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-ol with sodium hydride followed by reaction with 1-diethylamino-3-chloro-propane and, if the hydrogen fumarate salt is required, reacting the product with fumaric acid.
17. The compound 2-benzyl-2-(3'-diethylaminopropoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane or its hydrogen fumarate salt when prepared by a process according to claim 16 or an obvious chemical equivalent thereof.
18. A process as claimed in claim 1 wherein R is a benzyl group, A is an ethyl group and R1 and R2 are both ethyl groups.
19. A process for preparing 2-benzyl-2-(2'-diethylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane or its hydrogen fumarate salt which comprises reacting 2-benzyl-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-ol with sodium amide followed by reaction with 1-diethylamino-2-chloro-ethane and, if the hydrogen fumarate salt is required, reacting the product with fumaric acid.
20. The compound 2-benzyl-2-(2'-diethylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane or its hydrogen fumarate salt when prepared by a process according to claim 19 or an obvious chemical equivalent thereof.
21. A process as claimed in claim 1 wherein R is a phenyl group, A is a propylene group and R1 and R2 are both methyl groups.
22. A process for preparing 2-phenyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane or its hydrogen fumarate salt which comprises reacting 2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-ol with sodium amide followed by reaction with 1-dimethylamino-3-chloro-propane and, if the hydrogen fumarate salt is required, reacting the product with fumaric acid.
23. The compound 2-phenyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane or its hydrogen fumarate salt when prepared by a process according to claim 22 or an obvious chemical equivalent thereof.
24. A process as claimed in claim 1 wherein R is a phenyl group, A is an ethyl group and R1 and R2 are both methyl groups.
25. A process for preparing 2-phenyl-2-(2'-dimethylaminoethoxy)-2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]heptane or its hydrogen fumarate salt which com-prises reacting 2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-ol with potassium followed by reaction with 1-dimethylamino-2-chloro-ethane and, if the hydrogen fumarate salt is required, reacting the product with fumaric acid.
26. The compound 2-phenyl-2-(2'-dimethylaminoethoxy)-2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]heptane or its hydrogen fumarate salt when prepared by a process according to claim 25 or an obvious chemical equivalent thereof.
27. A process as claimed in claim 1 wherein R is a phenyl group, A is a propylene group and R1 and R2 are both ethyl groups.
28. A process for preparing 2-phenyl-2-(3'-diethylaminopropoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane or its hydrogen fumarate salt which comprises reacting 2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-ol with sodium amide, followed by reaction with l-diethylamino-3-chloro-propane and, if the hydrogen fumarate salt is required, reacting the product with fumaric acid.
29. The compound 2-phenyl-2-(3'-diethylaminopropoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane or its hydrogen fumarate salt when prepared by a process according to claim 28 or an obvious chemical equivalent thereof.
30. A process as claimed in claim 1 wherein R is a p-methoxyphenyl group, A is a propylene group and R1 and R2 are both methyl groups.
31. A process for preparing 2-(p-methoxyphenyl)-2-(3'-dimethylamino-propoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane or its hydrogen fumarate salt which comprises reacting 1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-one with a Grignard reagent obtained by reacting 4-bromoanisole with magnesium and decom-posing the product to form 2-(p-methoxyphenyl)-1,7,7-trimethyl-bicyclo[2.2.1]-heptan-2-ol, reacting this compound with sodium amide followed by 1-dimethyl-amino-3-chloro-propane and, if the hydrogen fumarate salt is required, reacting the product with fumaric acid.
32. The compound 2-(p-methoxyphenyl)-2-(3'-dimethylaminopropoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane or its hydrogen fumarate salt when prepared by a process according to claim 31 or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUEE-2715 | 1979-12-14 | ||
| HU79EE2715A HU179164B (en) | 1979-12-14 | 1979-12-14 | Process for producing cycloalkyl-ethers of alkanolamines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1155115A true CA1155115A (en) | 1983-10-11 |
Family
ID=10995882
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000366719A Expired CA1155115A (en) | 1979-12-14 | 1980-12-12 | Basic ethers, a process for their preparation and pharmaceutical compositions containing same |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US4342762A (en) |
| JP (1) | JPS56123953A (en) |
| AT (1) | AT374449B (en) |
| AU (1) | AU539173B2 (en) |
| BE (1) | BE886579A (en) |
| CA (1) | CA1155115A (en) |
| CH (1) | CH649986A5 (en) |
| CS (1) | CS216544B2 (en) |
| DD (1) | DD155320A5 (en) |
| DE (1) | DE3047142C2 (en) |
| DK (1) | DK156825C (en) |
| ES (1) | ES8200857A1 (en) |
| FI (1) | FI76783C (en) |
| FR (1) | FR2471968B1 (en) |
| GB (1) | GB2065122B (en) |
| GR (1) | GR72509B (en) |
| HU (1) | HU179164B (en) |
| IE (1) | IE51733B1 (en) |
| IL (1) | IL61685A (en) |
| IT (1) | IT1209377B (en) |
| NL (1) | NL193907C (en) |
| NO (1) | NO150638C (en) |
| PL (1) | PL127036B1 (en) |
| SE (1) | SE451132B (en) |
| SU (1) | SU1253425A3 (en) |
| UA (1) | UA5566A1 (en) |
| YU (1) | YU42367B (en) |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5242934A (en) * | 1992-03-02 | 1993-09-07 | R. J. Reynolds Tobacco Company | Method for treatment of neurodegenerative diseases |
| US5212188A (en) * | 1992-03-02 | 1993-05-18 | R. J. Reynolds Tabacco Company | Method for treatment of neurodegenerative diseases |
| US5242935A (en) * | 1992-03-06 | 1993-09-07 | R. J. Reynolds Tobacco Company | Method for treatment of neurodegenerative diseases |
| US5227385A (en) * | 1992-03-13 | 1993-07-13 | Wake Forest University | Method for treatment of neurodegenerative diseases |
| US5288872A (en) * | 1992-03-13 | 1994-02-22 | Wake Forest University | Compounds for treatment of neurodegenerative diseases |
| US5276043A (en) * | 1992-04-10 | 1994-01-04 | R. J. Reynolds Tobacco Company | Method for treatment of neurodegenerative diseases |
| US5214060A (en) * | 1992-04-10 | 1993-05-25 | R. J. Reynolds Tobacco Company | Method for treatment of neurodegenerative diseases |
| US5187169A (en) * | 1992-04-10 | 1993-02-16 | R. J. Reynolds Tobacco Company | Method for treatment of neurodegenerative diseases |
| US5232932A (en) * | 1992-05-21 | 1993-08-03 | R. J. Reynolds Tobacco Company | Method for treatment of neurodegenerative diseases |
| US5242916A (en) * | 1992-07-07 | 1993-09-07 | R. J. Reynolds Tobacco Company | Method for treatment of neurodegenerative diseases |
| US5248690A (en) * | 1992-07-07 | 1993-09-28 | R. J. Reynolds Tobacco Company | Method for treatment of neurodegenerative diseases |
| JPH0626170A (en) * | 1992-07-09 | 1994-02-01 | Yodogawa Steel Works Ltd | Mounting construction of wallboard |
| JPH06193226A (en) * | 1992-12-26 | 1994-07-12 | Yodogawa Steel Works Ltd | Installation structure for wall plate member |
| US5652270A (en) * | 1994-07-01 | 1997-07-29 | Egis Gyogyszergyar Rt | Pharmaceutical compositions containing bicycloheptane ether amines and a process for the preparation thereof |
| HU214588B (en) * | 1994-07-01 | 1998-04-28 | EGIS Gyógyszergyár Rt. | Process for producing pharmaceutical compositions comprising bicycloheptane derivative having cck system inhibitory effect |
| KR100381558B1 (en) * | 1994-07-01 | 2003-08-19 | 에지스 지오기스제르기아르 알티. | Pharmaceutical composition and preparation method thereof |
| US5583140A (en) * | 1995-05-17 | 1996-12-10 | Bencherif; Merouane | Pharmaceutical compositions for the treatment of central nervous system disorders |
| HU226061B1 (en) * | 1996-10-17 | 2008-04-28 | Egis Gyogyszergyar Nyilvanosan | 1,7,7-trimethyl-bicyclo[2.2.1]heptane derivative, pharmaceutical compositions containing the same and process for their preparation |
| HUP9900445A2 (en) * | 1999-02-24 | 2001-06-28 | EGIS Gyógyszergyár Rt. | Process for producing (1r,2s,4r)-(-)-n,n-(dimethylamino-ethoxy)-2-phenyl-1,7,7-trimethyl-bicyclo[2,2,1]heptane and intermediate of the same |
| HU227114B1 (en) * | 1999-05-11 | 2010-07-28 | Egis Gyogyszergyar Nyilvanosan | (1r, 2s, 4r)-(-)-2-[n,n-(dimethylamino-ethoxy)]-2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]heptane of high purity and pharmaceutically acceptable acid addition salts thereof, process for preparation of them and medicaments containing the same |
| FI20002612A0 (en) * | 2000-11-28 | 2000-11-28 | Orion Yhtymae Oyj | Combination therapy for the treatment of disorders in serotonin turnover |
| US6335372B1 (en) * | 2000-11-28 | 2002-01-01 | Orion Corporation | Treatment of obsessive compulsive disorder |
| HUP0103017A3 (en) * | 2001-07-18 | 2004-05-28 | Egis Gyogyszergyar Nyilvanosan | Pharmaceutical composition for the treatment of diseases caused by impairment of cognitive functions and its use |
| GB0306604D0 (en) * | 2003-03-21 | 2003-04-30 | Curidium Ltd | Second medical use |
| US20040192754A1 (en) * | 2003-03-24 | 2004-09-30 | Shapira Nathan Andrew | Methods for treating idiopathic hyperhidrosis and associated conditions |
| HUP0301537A3 (en) * | 2003-06-03 | 2005-07-28 | Egis Gyogyszergyar Nyilvanosan | Deramcyclane fumarate tablets and process for producing them |
| KR101493508B1 (en) * | 2013-02-18 | 2015-02-16 | 오스템임플란트 주식회사 | Tooth bleaching composition |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL246462A (en) * | 1959-08-06 | |||
| GB895050A (en) * | 1960-01-29 | 1962-04-26 | Boehringer & Soehne Gmbh | New basic ethers |
| DE1108684B (en) * | 1960-01-29 | 1961-06-15 | Boehringer & Soehne Gmbh | Process for the production of new basic ethers |
| AT264495B (en) * | 1963-08-18 | 1968-09-10 | Egyt Gyogyszervegyeszeti Gyar | Process for the production of new basic cycloheptanol ethers |
| GB1085969A (en) * | 1965-08-11 | 1967-10-04 | Glidden Co | Insectiphobic compositions comprising terpene derivatives |
| US4118499A (en) * | 1975-10-15 | 1978-10-03 | Glaxo Laboratories Limited | Anti-anxiety and anti-parkinsonian 1-aminoalkyl-2-endo-chloro-7,7-dimethylnorbornanes |
| JPS6034925B2 (en) * | 1979-07-31 | 1985-08-12 | 帝人株式会社 | Long-acting nasal preparation and its manufacturing method |
-
1979
- 1979-12-14 HU HU79EE2715A patent/HU179164B/en unknown
-
1980
- 1980-12-09 GB GB8039376A patent/GB2065122B/en not_active Expired
- 1980-12-10 YU YU3111/80A patent/YU42367B/en unknown
- 1980-12-10 SE SE8008680A patent/SE451132B/en not_active IP Right Cessation
- 1980-12-10 BE BE1/10069A patent/BE886579A/en not_active IP Right Cessation
- 1980-12-10 IL IL61685A patent/IL61685A/en not_active IP Right Cessation
- 1980-12-11 CS CS808736A patent/CS216544B2/en unknown
- 1980-12-11 JP JP17520880A patent/JPS56123953A/en active Granted
- 1980-12-11 CH CH9133/80A patent/CH649986A5/en not_active IP Right Cessation
- 1980-12-11 AT AT0601380A patent/AT374449B/en not_active IP Right Cessation
- 1980-12-11 PL PL1980228392A patent/PL127036B1/en unknown
- 1980-12-11 FR FR8026269A patent/FR2471968B1/en not_active Expired
- 1980-12-11 NL NL8006722A patent/NL193907C/en not_active IP Right Cessation
- 1980-12-11 DD DD80225942A patent/DD155320A5/en not_active IP Right Cessation
- 1980-12-11 US US06/215,154 patent/US4342762A/en not_active Expired - Lifetime
- 1980-12-11 DK DK528980A patent/DK156825C/en not_active IP Right Cessation
- 1980-12-11 AU AU65293/80A patent/AU539173B2/en not_active Expired
- 1980-12-11 FI FI803858A patent/FI76783C/en not_active IP Right Cessation
- 1980-12-12 NO NO803764A patent/NO150638C/en not_active IP Right Cessation
- 1980-12-12 GR GR63641A patent/GR72509B/el unknown
- 1980-12-12 SU SU3219704A patent/SU1253425A3/en active
- 1980-12-12 IE IE2612/80A patent/IE51733B1/en not_active IP Right Cessation
- 1980-12-12 UA UA3219704A patent/UA5566A1/en unknown
- 1980-12-12 IT IT8026587A patent/IT1209377B/en active
- 1980-12-12 CA CA000366719A patent/CA1155115A/en not_active Expired
- 1980-12-12 ES ES497717A patent/ES8200857A1/en not_active Expired
- 1980-12-15 DE DE3047142A patent/DE3047142C2/en not_active Expired
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